7H-pyrrolo[2,3-d]pyrimidine derivatives

ABSTRACT

The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives of formula I  
                 
 
     wherein the symbols and substituents are as defined in the description, to processes for the preparation thereof, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives—alone or in combination with one or more other pharmaceutically active compounds—for the preparation of pharmaceutical compositions for the treatment especially of a proliferative disease, such as a tumour.

7H-pyrrolo[2,3-d]pyrimidine derivatives

[0001] The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivativesand to processes for the preparation thereof, to pharmaceuticalcompositions comprising such derivatives and to the use of suchderivatives—alone or in combination with one or more otherpharmaceutically active compounds—for the preparation of pharmaceuticalcompositions for the treatment especially of a proliferative disease,such as a tumour.

[0002] The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivativesof formula I

[0003] wherein

[0004] R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic radicalbonded via a ring carbon atom, or a radical of the formula R₄—Y—(C═Z)-wherein R₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical, Y is either not present or lower alkyl and Z isoxygen, sulfur or imino, with the proviso that R₁ and R₂are not bothhydrogen; or

[0005] R₁ and R₂ together with the nitrogen atom to which they areattached form a heterocyclic radical;

[0006] R₃ is a heterocyclic radical or an unsubstituted or substitutedaromatic radical;

[0007] G is C₁-C₇-alkylene, —C(═O)—, or C₁-C₆-alkylene-C(═O)— whereinthe carbonyl group is attached to the NR₁R₂ moiety;

[0008] Q is —NH— or —O—, with the proviso that Q is —O— if G is-C(═O)—or C₁-C₆-alkylene-C(═O)—; and

[0009] X is either not present or C₁-C₇-alkylene, with the proviso thata heterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;

[0010] or a salt of the said compounds.

[0011] The general terms used hereinbefore and hereinafter preferablyhave within the context of this disclosure the following meanings,unless otherwise indicated:

[0012] Where the plural form is used for compounds, salts, and the like,this is taken to mean also a single compound, salt, or the like.

[0013] Where compounds of formula I are mentioned which can formtautomers, it is meant to include also the tautomers of such compoundsof formula I. In particular, tautomerism occurs e.g. for compounds offormula I which contain a 2-hydroxy-pyridyl radical (see e.g. radical R₃of the below-mentioned Examples 115-120). In such compounds the2-hydroxy-pyridyl radical can also be present as pyrid-2(1H)-on-yl.

[0014] Asymmetric carbon atoms of a compound of formula I that areoptionally present may exist in the (R), (S) or (R,S) configuration,preferably in the (R) or(S) configuration. Substituents at a double bondor a ring may be present in cis-(=Z-) or trans (=E-)form. The compoundsmay thus be present as mixtures of isomers or preferably as pureisomers.

[0015] Preferably alkyl contains up to 20 carbon atoms and is mostpreferably lower alkyl.

[0016] The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either unbranched or branched withsingle or multiple branching.

[0017] Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl or n-heptyl.

[0018] Alkyl R₁ and R₂ independently of each other are preferablymethyl, ethyl, isopropyl or tert-butyl, especially methyl or ethyl.

[0019] Lower alkyl Y is preferably methyl, ethyl or propyl.

[0020] Lower alkoxy is for example ethoxy or methoxy, especiallymethoxy.

[0021] Substituted alkyl is preferably lower alkyl as defined abovewhere one or more, preferably one, substituents may be present, such ase.g. amino, N-lower alkylamino, N,N-di-lower alkylamino, N-loweralkanoylamino, N,N-di-lower alkanoylamino, hydroxy, lower alkoxy, loweralkanoyl, lower alkanoyloxy, cyano, nitro, carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthio,halogen or a heterocyclic radical.

[0022] Substituted alkyl R₁ and R₂ are independently of each otherpreferably hydroxy-lower alkyl, N,N-di-lower alkylamino-lower alkyl ormorpholinyl-lower alkyl.

[0023] Preferably unsubstituted or substituted cycloalkyl R₁ or R₂contains from 3 up to 20 carbon atoms and is especially unsubstituted oralso substituted C₃-C₆ cycloalkyl wherein the substituents are selectedfrom e.g. unsubstituted or substituted lower alkyl, amino, N-loweralkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, N,N-di-loweralkanoylamino, hydroxy, lower alkoxy, lower alkanoyl, lower alkanoyloxy,cyano, nitro, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, amidino, guanidino,ureido, mercapto, lower alkylthio, halogen or a heterocyclic radical.

[0024] Mono- or disubstituted amino is amino substituted by one or tworadicals selected independently of one another from e.g. unsubstitutedor substituted lower alkyl.

[0025] Disubstituted amino R₄ is preferably N,N-di-lower alkylamino,especially N,N-dimethylamino or N,N-diethylamino.

[0026] A heterocyclic radical contains especially up to 20 carbon atomsand is preferably a saturated or unsaturated monocyclic radical havingfrom 4 or 8 ring members and from 1 to 3 heteroatoms which arepreferably selected from nitrogen, oxygen and sulfur, or a bi- ortri-cyclic radical wherein, for example, one or two carbocyclicradicals, such as e.g. benzene radicals, are annellated (fused) to thementioned monocyclic radical. If a heterocyclic radical contains a fusedcarbocyclic radical then the heterocyclic radical may also be attachedto the rest of the molecule of formula I via a ring atom of the fusedcarbocyclic radical. The heterocyclic radical (including the fusedcarbocyclic radical(s) if present) is optionally substituted by one ormore, preferably by one or two, radicals such as e.g. unsubstituted orsubstituted lower alkyl, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthio,or halogen.

[0027] Most preferably a heterocyclic radical is pyrrolidinyl,piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl, morpholinyl, tetrahydropyranyl, pyridyl, pyridylsubstituted by hydroxy or lower alkoxy, or benzodioxolyl, especiallypyrrolidinyl, piperidyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl or morpholinyl.

[0028] A heterocyclic radical R₁ or R₂ is as defined above for aheterocyclic radical with the proviso that it is bonded to the rest ofthe molecule of formula I via a ring carbon atom. Preferably aheterocyclic radical R₁ or R₂ is lower alkyl-piperazinyl or especiallypreferred tetrahydropyranyl. If one of the two radicals R₁ and R₂represents a heterocyclic radical, the other is preferably hydrogen.

[0029] A heterocyclic radical R₃ is as defined above for a heterocyclicradical with the proviso that it is bonded to Q via a ring carbon atomif X is not present. Preferably a heterocyclic radical R₃ isbenzodioxolyl, pyridyl substituted by hydroxy or lower alkoxy, orespecially preferred indolyl substituted by halogen and lower alkyl. IfR₃ is pyridyl substituted by hydroxy then the hydroxy group ispreferably attached to a ring carbon atom adjacent to the ring nitrogenatom.

[0030] A heterocyclic radical R₄ is as defined above for a heterocyclicradical and is preferably pyrrolidinyl, piperidyl, loweralkyl-piperazinyl, morpholinyl or pyridyl.

[0031] If R₁ and R₂ together with the nitrogen atom to which they areattached form a heterocyclic radical, the heterocyclic radical is asdefined above for a heterocyclic radical and represents preferablypyrrolidinyl, piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl or morpholinyl.

[0032] An unsubstituted or substituted aromatic radical R₃ has up to 20carbon atoms and is unsubstituted or substituted, for example in eachcase unsubstituted or substituted phenyl. Preferably an unsubstitutedaromatic radical R₃ is phenyl. A substituted aromatic radical R₃ ispreferably phenyl substituted by one or more substituents selectedindependently of one another from the group consisting of unsubstitutedor substituted lower alkyl, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthioand halogen. Most preferably a substituted aromatic radical R₃ is phenylsubstituted by one or more radicals selected independently of oneanother from the group consisting of lower alkyl, amino, hydroxy, loweralkoxy, halogen and benzyloxy.

[0033] Halogen is primarily fluoro, chloro, bromo or iodo, especiallyfluoro, chloro or bromo.

[0034] C₁-C₇-alkylene may be branched or unbranched and is in particularC₁-C₃-alkylene.

[0035] C₁-C₇-alkylene G is preferably C₁-C₃-alkylene, most preferablymethylene (—CH₂—).

[0036] If G is not C₁-C₇-alkylene it preferably represents —C(═O)—.

[0037] C₁-C₇-alkylene X is preferably C₁-C₃-alkylene, most preferablymethylene (—CH₂—) or ethan-1,1-diyl (—CH(CH₃)—).

[0038] Q is preferably —NH—.

[0039] Z is preferably oxygen or sulfur, most preferably oxygen.

[0040] Salts are especially the pharmaceutically acceptable salts ofcompounds of formula I.

[0041] Such salts are formed, for example, as acid addition salts,preferably with organic or inorganic acids, from compounds of formula Iwith a basic nitrogen atom, especially the pharmaceutically acceptablesalts.

[0042] In the presence of negatively charged radicals, such as carboxyor sulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, or ammoniumsalts with ammonia or suitable organic amines, such as tertiarymonoamines.

[0043] In the presence of a basic group and an acid group in the samemolecule, a compound of formula I may also form internal salts.

[0044] For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. Only the pharmaceutically acceptable salts or freecompounds (if the occasion arises, in the form of pharmaceuticalcompositions) attain therapeutic use, and these are therefore preferred.

[0045] In view of the close relationship between the novel compounds infree form and in the form of their salts, including those salts that canbe used as intermediates, for example in the purification oridentification of the novel compounds, hereinbefore and hereinafter anyreference to the free compounds is to be understood as referring also tothe corresponding salts, as appropriate and expedient.

[0046] The compounds of formula I have valuable, pharmacologicallyuseful properties. In particular they exhibit specific inhibitoryactivities that are of pharmacological interest. They are effectiveespecially as protein tyrosine kinase inhibitors and/or (furthermore) asinhibitors of serine/threonine protein kinases; they exhibit, forexample, powerful inhibition of the tyrosine kinase activity of theepidermal growth factor receptor (EGF-R) and of ErbB-2 kinase. These twoprotein tyrosine kinase receptors, together with their family membersErbB-3 and ErbB-4, play a key role in signal transmission in a largenumber of mammalian cells, including human cells, especially epithelialcells, cells of the immune system and cells of the central andperipheral nervous system. For example, in various cell types,EGF-induced activation of receptor-associated protein tyrosine kinase isa prerequisite for cell division and hence for the proliferation of thecell population. Most importantly, overexpression of the EGF-R (HER-1)and/or ErbB-2 (HER-2) has been observed in substantial fractions of manyhuman tumours. EGF-R, e.g., was found to be overexpressed in nonsmall-cell lung cancers, squameous carcinoma (head and neck), breast,gastric, ovarian, colon and prostate cancers as well as in gliomas.ErbB-2 was found to be overexpressed in squameous carcinoma (head andneck), breast, gastric, and ovarian cancers as well as in gliomas.

[0047] In addition to inhibiting the tyrosine kinase activity of theEGF-R, the compounds of formula I also inhibit to varying extents otherprotein tyrosine kinases that are involved in signal transmissionmediated by trophic factors, specially the vascular endothelial growthfactor (VEGF) receptor family (e.g. KDR, Fit-1, Flt-3) but also ablkinase, especially v-abl, kinases from the family of Src, especiallyc-Src, Lck and Fyn, the other members of the EGF receptor family such asErbB-3 (HER-3) and ErbB-4 (HER-4), CSF-1, Kit, FGF receptor and thecyclin-dependent kinases CDK1 and CDK2, all of which play a part ingrowth regulation and transformation in mammalian cells, including humancells.

[0048] The inhibition of EGF-R tyrosine kinase activity can bedemonstrated using known methods, for example using the recombinantintracellular domain of the EGF-receptor [EGF-R ICD; see, for example,E. McGlynn et al., Europ. J. Biochem. 207, 265-275 (1992)]. Comparedwith the control without inhibitor, the compounds of formula I inhibitthe enzyme activity by 50% (IC₅₀), for example in a concentration offrom 0.0005 to 0.5 μM, especially from 0.001 to 0.1 μM.

[0049] As well as or instead of inhibiting EGF-R tyrosine kinaseactivity, the compounds of formula I also inhibit other members of thisfamily of receptors, like ErbB-2. The inhibitory activity (IC₅₀) isapproximately in the range of 0.001 to 0.5 μM. The inhibition of ErbB-2tyrosine kinase (HER-2) can be determined, for example, analogously tothe method used for EGF-R protein tyrosine kinase [see C. House et al.,Europ. J. Biochem. 140, 363-367 (1984)]. The ErbB-2 kinase can beisolated, and its activity determined, by means of protocols known perse, for example in accordance with T. Akiyama et al., Science 232, 1644(1986).

[0050] Surprisingly, the compounds of formula I especially also inhibitthe tyrosine kinase activity of the VEGF receptor family very potently.The compounds of the present invention are therefore very effective dualinhibitors of EGF- and VEGF-receptor family members. For inhibition ofKDR and Flt-1 and inhibition of growth factor-induced proliferation ofHUVECS see J. Wood et al., Cancer Res. 60, 2178-2189 (2000). Thecompounds of formula I inhibit e.g. the KDR tyrosine kinase activitywith an IC₅₀ of from about 1 nM to about 1 μM, especially from about 5nM to about 0.5 μM.

[0051] The action of the compounds of formula I on EGF-inducedphosphorylation of the EGF-R can be determined in the human A431epithelial carcinoma cell line by means of an ELISA which is describedin U. Trinks et al., J. Med. Chem. 37.7, 1015-1027 (1994). In that test(EGF-R ELISA) the compounds of formula I exhibit an IC₅₀ ofapproximately from 0.001 to 1 μM.

[0052] The compounds of formula I potently inhibit the growth of EGF-Roverexpressing NCl-H596 non-small cell lung carcinoma cells [see e.g. W.Lei, et al., Anticancer Res. 19(1A), 221-228 (1999)] at an IC₅₀ ofapproximately 0.01 to 1 μM. In the same range of activity, the compoundsof formula I also potently inhibit the growth of ErbB-2-overexpressingBT474 human breast cancer cells. The test procedures are adapted from T.Meyer et al., Int. J. Cancer 43, 851 (1989). The inhibitory activity ofthe compounds of formula I is determined, briefly, as follows: NCl-H596cells (10,000/microtitre plate well) are transferred to 96-wellmicrotitre plates. The test compounds [dissolved in dimethyl sulfoxide(DMSO)] are added in a series of concentrations (dilution series) insuch a manner that the final concentration of DMSO is not greater than1% (v/v). After the addition, the plates are incubated for three daysduring which the control cultures without test compound are able toundergo at least three cell-division cycles. The growth of the NCl-H596cells is measured by means of methylene blue staining: after theincubation the cells are fixed with glutaraldehyde, washed with waterand stained with 0.05% methylene blue. After a washing step the stain iseluted with 3% HCI and the optical density (OD) per well of themicrotitre plate is measured using a Titertek Multiskan (Titertek,Huntsville, Ala., USA) at 665 nm. IC₅₀ values are determined by acomputer-aided system using the formula:

IC ₅₀=[(OD _(test) −OD _(start))/(OD _(control) −OD _(start))]×100.

[0053] The IC₅₀ value in those experiments is given as thatconcentration of the test compound in question that results in a cellcount that is 50% lower than that obtained using the control withoutinhibitor. The compounds of formula I exhibit inhibitory activity withan IC₅₀ in the range from approximately 0.01 to 1 μM.

[0054] The compounds of formula I exhibit inhibition of the growth oftumour cells also in vivo, as shown, for example, by the test describedbelow: the test is based on inhibition of the growth of the humansquamous lung carcinoma cell line NCl-H596 [ATCC HTB 178; American TypeCulture Collection, Rockville, Md., USA; see Santon, J. B., et al.,Cancer Research 46, 4701-4705 (1986) and Ozawa, S., et al., Int. J.Cancer 40, 706-710 (1987)], which is transplanted into female BALB/cnude mice (Bomholtgard, Denmark). That carcinoma exhibits a growth thatcorrelates with the extent of the expression of the EGF-R. Tumours areestablished after subcutaneous (s.c.) injection of cells [a minimum of2×10⁶ cells in 100 μl phosphate-buffered saline (PBS) or medium] incarrier mice (4-8 mice). Injections are made s.c. in the left flank ofthe mouse mid-way between the tail and the head. The resulting tumoursare serially passaged for a minimum of three consecutivetransplantations prior to start of the treatment. During this timetumour growth rates stabilize. Tumours are not passaged more than 12times. For the therapy experiment tumour fragments of roughly 25 mg aretransplanted s.c. into the left flank of the animals using a 13-gaugetrocar needle under Forene® (Abbott, Schwitzerland) anesthesia. Tumourgrowth and body weights are monitored twice per week. All treatments areinitiated when the tumour attains a volume of 100 to 250 mm³. The tumourvolumes are calculated using the known formula Length×Diameter²×π/6 [seeEvans, B. D., et al., Brit. J. Cancer 45, 466-8 (1982)]. Antitumouractivity is expressed as T/C % (mean increase of tumour volumes oftreated animals divided by the mean increase of tumour volumes ofcontrol animals multiplied by 100%). At a dose of from 3 to 100 mg/kg ofactive ingredient, distinct inhibition of the tumour growth is found,for example T/C % values of less than 50.

[0055] The compounds of formula I may inhibit other protein tyrosinekinases that are involved in signal transmission mediated by trophicfactors, for example abl kinase, such as especially v-abl kinase (IC₅₀for example from 0.01 to 5 μM), kinases from the family of the srckinases, such as especially c-src kinase (IC₅₀ for example from 0.1 to10 μM) and serine/threonine kinases, for example protein kinase C, allof which are involved in growth regulation and transformation inmammalian cells, including human cells.

[0056] The above-mentioned inhibition of v-abl tyrosine kinase isdetermined by the methods of N. Lydon et al., Oncogene Research 5,161-173 (1990) and J. F. Geissler et al., Cancer Research 52, 4492-4498(1992). In those methods [Val⁵]-angiotensin II and [γ³²P]-ATP are usedas substrates.

[0057] The compounds of formula I which inhibit the tyrosine kinaseactivity of the EGF-R or of the other protein tyrosine kinases mentionedare therefore useful, for example, in the treatment of benign ormalignant tumours. The compounds of formula I are e.g. able tosimultaneously inhibit the growth of tumors with deregulated EGF-Rand/or ErbB-2 activity as well as to inhibit the vascularisation ofsolid tumors triggered by VEGF. This combined activity leads to animproved antitumour effect (see also WO 02/41882). Moreover, the use ofa dual inhibitor reduces the risk of drug-drug interactions and furtherreduces the total drug load as compared to a combination therapy. Thecompounds of formula I are capable of slowing down tumor growth oreffecting tumour regression and of preventing the formation of tumourmetastases and the growth of micrometastases. They can be usedespecially in the case of epidermal hyperproliferation (psoriasis), inthe treatment of neoplasias of epithelial character, e.g. mammarycarcinomas, and in leukaemias. In addition, the compounds of formula Ican be used in the treatment of those disorders of the immune system inwhich several or, especially, individual protein tyrosine kinases and/or(furthermore) serine/threonine protein kinases are involved; thecompounds of formula I can also be used in the treatment of thosedisorders of the central or peripheral nervous system in which signaltransmission by several or, especially, a single protein tyrosinekinase(s) and/or (furthermore) serine/threonine protein kinase(s) is/areinvolved.

[0058] In general, the present invention relates also to the use of thecompounds of formula I for the inhibition of the mentioned proteinkinases, in particular to their use for the dual inhibition of EGF- andVEGF-receptor family members.

[0059] The compounds according to the invention can be used both aloneand in combination with other pharmacologically active compounds, forexample together with inhibitors of the enzymes of polyamine synthesis,inhibitors of protein kinase C, inhibitors of other tyrosine kinases,cytokines, negative growth regulators, for example TGF-β or IFN-β,aromatase inhibitors, antioestrogens and/or cytostatic drugs.

[0060] With the groups of preferred compounds of formula I mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replacemore general definitions with more specific definitions or especiallywith definitions characterized as being preferred.

[0061] Preference is given to a compound of formula I, wherein

[0062] R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic radicalbonded via a ring carbon atom, or a radical of the formula R₄—Y—(C=Z)-wherein R₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical, Y is either not present or lower alkyl and Z isoxygen or sulfur or imino, with the proviso that R₁ and R₂ are not bothhydrogen; or

[0063] R₁ and R₂ together with the nitrogen atom to which they areattached form a heterocyclic radical;

[0064] R₃ is a heterocyclic radical or an unsubstituted or substitutedaromatic radical;

[0065] G is C₁-C₇-alkylene;

[0066] Q is —NH— or —O—; and

[0067] X is either not present or C₁-C₇-alkylene, with the proviso thata heterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;

[0068] or a salt thereof.

[0069] Preference is further given to a compound of formula I, wherein

[0070] R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic radicalbonded via a ring carbon atom, or a radical of the formula R₄—Y—(C=Z)-wherein R₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical, Y is either not present or lower alkyl and Z isoxygen, sulfur or imino, with the proviso that R₁ and R₂ are not bothhydrogen; or

[0071] R₁ and R₂ together with the nitrogen atom to which they areattached form a heterocyclic radical;

[0072] R₃ is a heterocyclic radical or an unsubstituted or substitutedaromatic radical;

[0073] G is C₁-C₇alkylene;

[0074] Q is —NH—; and

[0075] X is either not present or C₁-C₇-alkylene, with the proviso thata heterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;

[0076] or a salt thereof.

[0077] Special preference is given to a compound of formula 1, wherein

[0078] R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted lower alkyl or C₃-C₆ cycloalkyl, aheterocyclic radical bonded via a ring carbon atom and containing up to20 carbon atoms, or a radical of the formula R₄—Y—(C=Z)- wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radicalcontaining up to 20 carbon atoms, Y is either not present or lower alkyland Z is oxygen, with the proviso that R₁ and R₂ are not both hydrogen;or

[0079] R₁ and R₂ together with the nitrogen atom to which they areattached form a heterocyclic radical containing up to 20 carbon atoms;

[0080] R₃ is a heterocyclic radical containing up to 20 carbon atoms oran unsubstituted or substituted aromatic radical having up to 20 carbonatoms;

[0081] G is C₁-C₃-alkylene;

[0082] Q is —NH—; and

[0083] X is either not present or C₁-C₃-alkylene, with the proviso thata heterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;

[0084] or a salt thereof.

[0085] Special preference is further given to a compound of formula I,wherein

[0086] R₁ and R₂ are each independently of the other hydrogen, loweralkyl, hydroxy-lower alkyl, N,N-di-lower alkylamino-lower alkyl,morpholinyl-lower alkyl, tetrahydropyranyl, or a radical of the formulaR₄—Y—(C=Z)- wherein R₄ is di-lower alkylamino, pyrrolidinyl, piperidyl,lower alkyl-piperazinyl, morpholinyl or pyridyl, Y is either not presentor lower alkyl and Z is oxygen, with the proviso that R₁ and R₂ are notboth hydrogen; or

[0087] R₁ and R₂ together with the nitrogen atom to which they areattached form a radical selected from the group consisting ofpyrrolidinyl, piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl and morpholinyl;

[0088] R₃ is phenyl, benzodioxolyl, pyridyl substituted by hydroxy orlower alkoxy, indolyl substituted by halogen and lower alkyl, or phenylsubstituted by one or more radicals selected independently of oneanother from the group consisting of lower alkyl, hydroxy, lower alkoxy,halogen and benzyloxy;

[0089] G is —CH₂— or —C(═O)—;

[0090] Q is —NH— or —O—, with the proviso that Q is —O— if G is —C(═O)—;and

[0091] X is either not present, —CH₂— or —CH(CH₃)—, with the provisothat substituted pyridyl or indolyl R₃ is bonded via a ring carbon atomif X is not present;

[0092] or a salt thereof.

[0093] Special preference is further also given to a compound of formulaI, wherein

[0094] R₁ and R₂ are each independently of the other hydrogen, loweralkyl, hydroxy-lower alkyl, or a radical of the formula R₄—Y—(C=Z)-wherein R₄ is di-lower alkylamino, pyrrolidinyl, piperidyl, loweralkyl-piperazinyl, morpholinyl or pyridyl, Y is either not present orlower alkyl and Z is oxygen, with the proviso that R₁ and R₂ are notboth hydrogen; or

[0095] R₁ and R₂ together with the nitrogen atom to which they areattached form a radical selected from the group consisting ofpyrrolidinyl, piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl and morpholinyl;

[0096] R₃ is phenyl, benzodioxolyl, pyridyl substituted by hydroxy orlower alkoxy, or phenyl substituted by one or more radicals selectedindependently of one another from the group consisting of lower alkyl,hydroxy, lower alkoxy, halogen and benzyloxy;

[0097] G is —CH₂—;

[0098] Q is —NH—; and

[0099] X is either not present, —CH₂— or —CH(CH₃)—, with the provisothat substituted pyridyl R₃ is bonded via a ring carbon atom if X is notpresent;

[0100] or a salt thereof.

[0101] Special preference is also given to a compound of formula Iwherein C₁-C₇-alkylene G is attached to the phenyl ring at position 3 or4, most especially at position 4.

[0102] Very special preference is further given to a compound of formulaI mentioned in the Examples below, or a salt, especially apharmaceutically acceptable salt, thereof.

[0103] Also especially preferred are compounds of formula I,which—according to the above-described tyrosine kinase inhibitionassays—inhibit HER-1, HER-2 and KDR with IC₅₀ values of less than 300nM, most preferably of less than 100 nM.

[0104] Very special preference is further given to compounds of formulaI which inhibit the tyrosine kinase activity of at least one member ofthe EGF receptor family together with at least one member of the VEGFreceptor family (dual inhibition of EGF- and VEGF-receptor familymembers) with IC₅₀ values in the range of 0.5 nM to 0.5 μM, especiallyin the range of 1 nM to 300 nM, based on the above-described tyrosinekinase inhibition assays.

[0105] Especially preferred are further also compounds of formula I inwhich G is C₁-C₇-alkylene since the amine group of such compounds allowsto generate pharmaceutically acceptable salts of these compounds whichin general leads to an increased solubility and to improvedphysico-chemical properties.

[0106] The compounds of formula I or salts thereof are prepared inaccordance with processes known per se (see also EP 682 027, WO97/02266, WO 97/27199 and WO 98/07726), though not previously describedfor the manufacture of the compounds of the formula I, especiallywhereby

[0107] a) in order to prepare a compound of formula I, wherein G isC₁-C₇-alkylene and wherein R₁ and R₂ are each independently of the otherhydrogen, unsubstituted or substituted alkyl or cycloalkyl, or aheterocyclic radical bonded via a ring carbon atom, with the provisothat R₁ and R₂ are not both hydrogen, or wherein R₁ and R₂ together withthe nitrogen atom to which they are attached form a heterocyclicradical, a compound of the formula II

[0108] wherein Hal is halogen, G is C₁-C₇-alkylene and R₃, Q and X havethe meanings as defined for a compound of formula I, is reacted with acompound of the formula III

[0109] wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, or a heterocyclicradical bonded via a ring carbon atom, with the proviso that R₁ and R₂are not both hydrogen, or wherein R₁ and R₂ together with the nitrogenatom to which they are attached form a heterocyclic radical;

[0110] b) in order to prepare a compound of formula I, wherein G isC₁-C₇-alkylene and wherein R₁ is a radical of the formula R₄—Y—(C=Z)-wherein R₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical, Y is either not present or lower alkyl and Z isoxygen or sulfur,

[0111] (i) a compound of the formula IV

[0112] wherein Hal is halogen, G is C₁-C₇-alkylene, Z is oxygen and theremaining substituents and symbols have the meanings as defined for acompound of formula I according to claim 1, is reacted with a compoundof the formula R₄-H wherein R₄ is unsubstituted, mono- or disubstitutedamino or a heterocyclic radical containing at least one nitrogen ringatom wherein the heterocyclic radical is attached to the hydrogen atomof R₄-H via a nitrogen ring atom, or

[0113] (ii) a compound of the formula V

[0114] wherein G is C₁-C₇-alkylene and the remaining substituents andsymbols have the meanings as defined for a compound of formula I, isreacted with a compound of the formula VI

[0115] wherein R₄ and Y have the meanings as defined above under formulaI and Z is oxygen,

[0116] whereby a compound of formula I which results from process b) (i)or (ii) is optionally converted into the respective compound wherein Zis sulfur;

[0117] c) in order to prepare a compound of formula I, wherein G is—C(═O)— or C₁-C₆-alkylene-C(═O)— wherein the carbonyl group is attachedto the NR₁R₂ moiety, a compound of formula XI

[0118] wherein the substituents and symbols have the meanings as definedfor a compound of formula I, is reacted with a compound of formula XII

[0119] wherein R₁ and R₂ have the meanings as defined for a compound offormula I; or

[0120] d) in order to prepare a compound of formula I, wherein G isC₁-C₇-alkylene, a compound of formula I, wherein G is —C(═O)— orC₁-C₆-alkylene-C(═O)— wherein the carbonyl group is attached to theNR₁R₂ moiety, is reacted with a reducing agent to produce thecorresponding compound in which G is C₁-C₇-alkylene;

[0121] whereby functional groups which are present in the startingcompounds of processes a) to d) and are not intended to take part in thereaction, are present in protected form if necessary, and protectinggroups that are present are cleaved, whereby the said starting compoundsmay also exist in the form of salts provided that a salt-forming groupis present and a reaction in salt form is possible;

[0122] and, if so desired, a compound of formula I thus obtained isconverted into another compound of formula I, a free compound of formulaI is converted into a salt, an obtained salt of a compound of formula Iis converted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula I is separated into the individualisomers.

[0123] Description of the Process Variants:

[0124] Regarding Process a):

[0125] The reaction between a compound of formula II and a compound offormula III preferably takes place in a suitable inert solvent,especially N,N-dimethylformamide, in the presence of a base such aspotassium carbonate, at temperatures from room temperature (RT) to 100°C. Alternatively, the reaction between a compound of formula II and acompound of formula III takes place in a suitable solvent, e.g. loweralcohols, such as ethanol, in the presence of for example a suitablecatalyst such as Nal, preferably at the reflux temperature of thesolvent employed. In a compound of formula II, Hal is preferably chloro.

[0126] Regarding Process b):

[0127] (i) The reaction of a compound of formula IV and a compound ofthe formula R₄—H preferably takes place in a suitable solvent,especially alcohols, e.g. lower alcohols such as n-butanol, at elevatedtemperature, preferably near the boiling temperature of the solventemployed. In a compound of formula IV, Hal is preferably chloro.

[0128] (ii) The reaction between a compound of formula V and a compoundof formula VI preferably takes place in the presence ofO-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium-tetrafluroborate(TPTU) and N,N-diisopropylethylamine, or in the presence of(benzotriazole-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluoroborate(BOP) and N-methylmorpholin, in a suitable inert solvent, such as forexample N,N-dimethylformamide, preferably at RT.

[0129] A compound of formula I which results from process b) (i) or (ii)can be converted into the respective compound of formula I wherein Z issulfur, for example, by using an appropriate sulfur compound, e.g. usingreaction with Lawesson's reagent(2,4-bis-(4-methoxyphenyl)2,4-dithioxo-1,2,3,4-dithia-phosphetan) in ahalogenated carbon hydrate, such as dichloromethane, or an aproticsolvent, such as toluene or xylene, at temperatures from about 30° C. toreflux.

[0130] Regarding Process c):

[0131] The reaction of a compound of formula XI with a compound offormula XII preferably takes place in a suitable inert solvent such asN,N-dimethylformamide and in an inert, for example an argon or nitrogen,atmosphere, in the presence of diethyl-cyanphosphonate, preferably atabout 0° C.

[0132] Regarding Process d):

[0133] The reducing agent used in process d) is preferably lithiumaluminium hydride or diisobutyl-aluminium hydride. The reactionpreferably takes place under those conditions described in Example 79 or141, respectively.

[0134] Additional Process Steps

[0135] In the additional process steps, carried out as desired,functional groups of the starting compounds which should not take partin the reaction may be present in unprotected form or may be protectedfor example by one or more protecting groups. The protecting groups arethen wholly or partly removed according to one of the known methods.

[0136] Protecting groups, and the manner in which they are introducedand removed are described, for example, in “Protective Groups in OrganicChemistry”, Plenum Press, London, New York 1973, and in “Methoden derorganischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1,Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene,“Protective Groups in Organic Synthesis”, John Wiley & Sons, New York1981. A characteristic of protecting groups is that they can be removedreadily, i.e. without the occurrence of undesired secondary reactions,for example by solvolysis, reduction, photolysis or alternatively underphysiological conditions.

[0137] The end products of formula I may however also containsubstituents that can also be used as protecting groups in startingmaterials for the preparation of other end products of formula I. Thus,within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of formula I isdesignated a “protecting group”, unless the context indicates otherwise.

[0138] General Process Conditions

[0139] All process steps described here can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably those that are inert to the reagents used and able todissolve them, in the absence or presence of catalysts, condensingagents or neutralising agents, for example ion exchangers, typicallycation exchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at RT, at−20to 40° C., at 0 to 100° C. or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, if need be underpressure, and/or in an inert, for example an argon or nitrogen,atmosphere.

[0140] The invention relates also to those embodiments of the process inwhich one starts from a compound obtainable at any stage as anintermediate and carries out the missing steps, or breaks off theprocess at any stage, or forms a starting material under the reactionconditions, or uses said starting material in the form of a reactivederivative or salt, or produces a compound obtainable by means of theprocess according to the invention under those process conditions, andfurther processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described hereinabove as preferred.

[0141] In the preferred embodiment, a compound of formula I is preparedaccording to the processes and process steps defined in the Examples.

[0142] The compounds of formula I, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallisation (present as solvates).

[0143] Starting Materials

[0144] New starting materials and/or intermediates, as well as processesfor the preparation thereof, are likewise the subject of this invention.In the preferred embodiment, such starting materials are used andreaction conditions so selected as to enable the preferred compounds tobe obtained.

[0145] The starting materials used in the above described processes a)to b) are known, capable of being prepared according to known processes(see also EP 682 027, WO 97/02266, WO 97/27199 and WO 98/07726), orcommercially obtainable; in particular, they can be prepared usingprocesses as described in the Examples.

[0146] In the preparation of starting materials, existing functionalgroups which do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the Examples. In place of therespective starting materials and transients, salts thereof may also beused for the reaction, provided that salt-forming groups are present andthe reaction with a salt is also possible. Where the term startingmaterials is used hereinbefore and hereinafter, the salts thereof arealways included, insofar as reasonable and possible.

[0147] A compound of formula II can be prepared for example by reactinga compound of formula VII

[0148] wherein G is C₁-C₇-alkylene and R₃, Q and X have the meanings asdefined for a compound of formula I, with e.g. thionyl halogenide,preferably thionyl choride, in the presence or absence of pyridine, inan inert solvent, for example toluene or in a 1:1 mixture ofacetonitrile and dioxane, preferably at −10to 0° C. or at RT.

[0149] A compound of formula VII can be prepared for example by reactinga compound of formula VIII

[0150] wherein R₅ is lower alkyl, especially methyl or ethyl, and R₃, Qand X have the meanings as defined for a compound of formula I, withlithium aluminium hydride, in an inert solvent, especially ethers, e.g.cyclic ethers such as tetrahydrofuran, preferably at the refluxtemperature of the solvent employed. Alternatively, a compound offormula VII may be prepared by reacting a compound of formula VIII withdiisobutyl-aluminium hydride, in an inert solvent, for example intetrahydrofuran or in a 1:1 mixture of dichloromethane and dioxane,preferably at RT.

[0151] A compound of formula VIII wherein Q is —NH— can be prepared forexample by reacting a compound of formula IX

[0152] wherein Hal is halogen, preferably chloro, and R₅ is as definedabove for a compound of formula VIII, with a compound of the formulaH₂N—X—R₃, wherein R₃ and X have the meanings as defined for a compoundof formula I, (i) in a suitable solvent such as alcohols, especiallylower alcohols such as n-butanol, preferably at the boiling temperatureof the solvent employed or (ii) under catalytic conditions e.g.according to the Buchwald reaction conditions such as those described inStep 133.1 of Example 133 below.

[0153] A compound of formula VIII wherein Q is —O— can be prepared forexample by reacting a compound of formula IX, which is preferablyN-protected in the pyrrolo-pyrimidine moiety, with a compound of theformula HO—X—R₃, wherein R₃ and X have the meanings as defined for acompound of formula I, in a suitable inert solvent such asN,N-dimethylformamide and in the presence of a base such as potassiumcarbonate, at elevated temperatures, preferably at around 100° C.

[0154] Alternatively, the carboxylic acid ester of a compound of formulaIX may first be reduced to the corresponding alcohol, e.g. underconditions described above for the preparation of a compound of formulaVII, and then either be reacted with a compound of the formula H₂N—X—R₃,e.g. under conditions described above for the preparation of a compoundof formula VIII wherein Q, is —NH—, or be reacted with a compound of theformula HO—X—R₃, e.g. under conditions described above for thepreparation of a compound of formula VIII wherein Q is —O—.

[0155] A compound of formula IV can be prepared for example by reactinga compound of formula V with a compound of the formula X

[0156] wherein Hal is Halogen, preferably chloro, Y has the meanings asdefined above under formula I, and Z is oxygen, in the presence oftriethylamine, in an inert solvent such as e.g. tetrahydrofuran,preferably at RT.

[0157] A compound of formula XI can be prepared for example by reactinga compound of formula VIII with LiOH, preferably in a mixture of dioxaneand water, at elevated temperatures, preferably under those conditionsdescribed in Step 141.4 of Example 141 below.

[0158] The remaining starting materials are known, capable of beingprepared according to known processes, or commercially available; or inparticular, they can be prepared using processes as described in theExamples.

[0159] Pharmaceutical Compositions, Methods, and uses

[0160] The present invention relates also to pharmaceutical compositionsthat comprise a compound of formula I, or a pharmaceutically acceptablesalt thereof, as active ingredient and that can be used especially inthe treatment of the diseases mentioned at the beginning. Compositionsfor enteral administration, such as nasal, buccal, rectal or,especially, oral administration, and for parenteral administration, suchas intravenous, intramuscular or subcutaneous administration, towarm-blooded animals, especially humans, are especially preferred. Thecompositions contain the active ingredient alone or, preferably,together with a pharmaceutically acceptable carrier. The dosage of theactive ingredient depends upon the disease to be treated and upon thespecies, its age, weight, and individual condition, the individualpharmacokinetic data, and the mode of administration.

[0161] The present invention also relates to pro-drugs of a compound offormula I that convert in vivo to the compound of formula I as such. Anyreference to a compound of formula I is therefore to be understood asreferring also to the corresponding pro-drugs of the compound of formulaI, as appropriate and expedient.

[0162] The invention relates also to compounds of formula I, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition, for use in a method for the prophylactic orespecially therapeutic treatment of the human or animal body, to aprocess for the preparation thereof (especially in the form ofcompositions for the treatment of tumours) and to a method of treatingproliferative diseases, primarily tumour diseases, especially thosementioned above.

[0163] The invention relates also to processes and to the use ofcompounds of formula I, or a pharmaceutically acceptable salt thereof,for the preparation of pharmaceutical compositions which comprisecompounds of formula I, or a pharmaceutically acceptable salt thereof,as active component (active ingredient).

[0164] If desired, the said pharmaceutical compositions may also containfurther active components, for example cytostatics, and/or may be usedin combination with known therapeutic processes, for example theadministration of hormones or radiation.

[0165] Preference is given for a pharmaceutical composition which issuitable for administration to a warm-blooded animal, especially humansor commercially useful mammals suffering from a disease which respondsto an inhibition of a protein tyrosine kinase, especially to a dualinhibition of EGF- and VEGF-receptor family members, especially aneoplastic disease, comprising an effective quantity of a compound offormula I for the inhibition of a protein tyrosine kinase, especiallyfor the dual inhibition of EGF- and VEGF-receptor family members, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier.

[0166] A pharmaceutical composition for the prophylactic or especiallytherapeutic management of neoplastic and other proliferative diseases ofa warm-blooded animal, especially a human or a commercially usefulmammal requiring such treatment, especially suffering from such adisease, comprising as active ingredient in a quantity that isprophylactically or especially therapeutically active against saiddiseases a compound of formula I, or a pharmaceutically acceptable saltthereof, is likewise preferred.

[0167] The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories or capsules. Examples are capsules containing from about0.05 g to about 1.0 g of active substance.

[0168] The pharmaceutical compositions of the present invention areprepared in a manner known per se, for example by means of conventionalmixing, granulating, coating, dissolving or lyophilising processes.

[0169] The invention relates likewise to a process or a method for thetreatment of one of the pathological conditions mentioned hereinabove,especially a disease which responds to an inhibition of a proteintyrosine kinase, especially to a dual inhibition of EGF- andVEGF-receptor family members, especially a corresponding neoplasticdisease. The compounds of formula I, or pharmaceutically acceptablesalts thereof, can be administered as such or in the form ofpharmaceutical compositions, prophylactically or therapeutically,preferably in an amount effective against the said diseases, to awarm-blooded animal, for example a human, requiring such treatment, thecompounds especially being used in the form of pharmaceuticalcompositions. In the case of an individual having a bodyweight of about70 kg the daily dose administered is from approximately 0.1 g toapproximately 5 g, preferably from approximately 0.5 g to approximately2 g, of a compound of the present invention.

[0170] The present invention relates especially also to the use of acompound of formula I, or a pharmaceutically acceptable salt thereof,especially a compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition with at least one pharmaceutically acceptablecarrier, for the therapeutic and also prophylactic management of one ormore of the diseases mentioned hereinabove, preferably a disease whichresponds to an inhibition of a protein tyrosine kinase, especially to adual inhibition of EGF- and VEGF-receptor family members, especially aneoplastic disease, in particular if the said disease responds to aninhibition of a protein tyrosine kinase, especially to a dual inhibitionof EGF- and VEGF-receptor family members.

[0171] The present invention relates especially also to the use of acompound of formula I, or a pharmaceutically acceptable salt thereof,especially a compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the therapeutic and also prophylacticmanagement of one or more of the diseases mentioned hereinabove,especially a neoplastic disease, in particular if the disease respondsto an inhibition of a protein tyrosine kinase, especially to a dualinhibition of EGF- and VEGF-receptor family members.

[0172] A compound of formula I may also be used to advantage incombination with other antiproliferative agents. Such antiproliferativeagents include, but are not limited to aromatase inhibitors,antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors,microtubule active agents, alkylating agents, histone deacetylaseinhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMPinhibitors, mTOR inhibitors, antineoplastic antimetabolites, platincompounds, compounds decreasing the protein kinase activity and furtheranti-angiogenic compounds, gonadorelin agonists, anti-androgens,bengamides, bisphosphonates, antiproliferative antibodies andtemozolomide (TEMODAL®).

[0173] The term “aromatase inhibitors” as used herein relates tocompounds which inhibit the estrogen production, i.e. the conversion ofthe substrates androstenedione and testosterone to estrone andestradiol, respectively. The term includes, but is not limited tosteroids, especially exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, vorozole, fadrozole,anastrozole and, very especially, letrozole. Exemestane can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark AROMASIN™. Formestane can be administered, e.g., in the formas it is marketed, e.g. under the trademark LENTARON™. Fadrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark AFEMA™. Anastrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark ARIMIDEX™. Letrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FEMARA™ or FEMAR™. Aminoglutethimide can be administered,e.g., in the form as it is marketed, e.g. under the trademark ORIMETEN™.

[0174] A combination of the invention comprising an antineoplastic agentwhich is an aromatase inhibitor is particularly useful for the treatmentof hormone receptor positive breast tumors.

[0175] The term “antiestrogens” as used herein relates to compoundswhich antagonize the effect of estrogens at the estrogen receptor level.The term includes, but is not limited to tamoxifen, fulvestrant,raloxifene and raloxifene hydrochloride. Tamoxifen can be administered,e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX™.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA™. Fulvestrant can beformulated as disclosed in U.S. Pat. No. 4,659,516 or it can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FASLODEX™.

[0176] The term “topoisomerase I inhibitors” as used herein includes,but is not limited to topotecan, irinotecan, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148 (compound Al inWO99/17804). Irinotecan can be administered, e.g., in the form as it ismarketed, e.g. under the trademark CAMPTOSAR™. Topotecan can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HYCAMTIN™.

[0177] The term “topoisomerase II inhibitors” as used herein includes,but is not limited to the antracyclines doxorubicin (including liposomalformulation, e.g. CAELYX™), epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinesetoposide and teniposide. Etoposide can be administered, e.g., in theform as it is marketed, e.g. under the trademark ETOPOPHOS™. Teniposidecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark VM 26-BRISTOL™. Doxorubicin can be administered, e.g., in theform as it is marketed, e.g. under the trademark ADRIBLASTIN™.Epirubicin can be administered, e.g., in the form as it is marketed,e.g. under the trademark FARMORUBICIN™. Idarubicin can be administered,e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOS™.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g. under the trademark NOVANTRON™.

[0178] The term “microtubule active agents” relates to microtubulestabilizing and microtubule destabilizing agents including, but notlimited to the taxanes paclitaxel and docetaxel, the vinca alkaloids,e.g., vinblastine, especially vinblastine sulfate, vincristineespecially vincristine sulfate, and vinorelbine, discodermolide andepothilones, such as epothilone B and D. Docetaxel can be administered,e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE™.Vinblastine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark VINBLASTIN R.P.™. Vincristine sulfatecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark FARMISTIN™. Discodermolide can be obtained, e.g., as disclosedin U.S. Pat. No. 5,010,099.

[0179] The term “alkylating agents” as used herein includes, but is notlimited to cyclophosphamide, ifosfamide and melphalan. Cyclophosphamidecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CYCLOSTIN™. Ifosfamide can be administered, e.g., in the formas it is marketed, e.g. under the trademark HOLOXAN™.

[0180] The term “histone deacetylase inhibitors” relates to compoundswhich inhibit the histone deacetylase and which possessantiproliferative activity.

[0181] The term “farnesyl transferase inhibitors” relates to compoundswhich inhibit the farnesyl transferase and which possessantiproliferative activity.

[0182] The term “COX-2 inhibitors” relates to compounds which inhibitthe cyclooxygenase type 2 enyzme (COX-2) and which possessantiproliferative activity such as celecoxib (Celebrex®), rofecoxib(Vioxx®) and lumiracoxib (COX189).

[0183] The term “MMP inhibitors” relates to compounds which inhibit thematrix metalloproteinase (MMP) and which possess antiproliferativeactivity.

[0184] The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

[0185] The term “antineoplastic antimetabolites” includes, but is notlimited to 5-fluorouracil, tegafur, capecitabine, cladribine,cytarabine, fludarabine phosphate, fluorouridine, gemcitabine,6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts ofsuch compounds, and furthermore ZD 1694 (RALTITREXED™), LY231514(ALIMTA™), LY264618 (LOMOTREXOL™) and OGT719.

[0186] The term “platin compounds” as used herein includes, but is notlimited to carboplatin, cis-platin and oxaliplatin. Carboplatin can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN™.

[0187] The term “compounds decreasing the protein kinase activity andfurther anti-angiogenic compounds” as used herein includes, but is notlimited to compounds which³ decrease the activity of e.g. the VascularEndothelial Growth Factor (VEGF), the Epidermal Growth Factor (EGF),c-Src, protein kinase C, Platelet-derived Growth Factor (PDGF), Bcr-Abltyrosine kinase, c-kit, Flt-3 and Insulin-like Growth Factor I Receptor(IGF-IR) and Cyclin-dependent kinases (CDKs), and anti-angiogeniccompounds having another mechanism of action than decreasing the proteinkinase activity.

[0188] Compounds which decrease the activity of VEGF are especiallycompounds which inhibit the VEGF receptor, especially the tyrosinekinase activity of the VEGF receptor, and compounds binding to VEGF, andare in particular those compounds, proteins and monoclonal antibodiesgenerically and specifically disclosed in WO 98/35958 (describingcompounds of formula 1), WO 00/09495, WO 00/27820, WO 00/59509, WO98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0 769 947; thoseas described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218,by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp.14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998,3209-3214, and by J. Mordenti et al in Toxicologic Pathology, vol. 27,no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202; Angiostatin™,described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; andEndostatin™, described by M. S. O'Reilly et al, Cell 88, 1997, 277-285;

[0189] compounds which decrease the activity of EGF are especiallycompounds which inhibit the EGF receptor, especially the tyrosine kinaseactivity of the EGF receptor, and compounds binding to EGF, and are inparticular those compounds generically and specifically disclosed in WO97/02266 (describing compounds of formula IV), EP 0 564 409, WO99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, WO98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO96/33980;

[0190] compounds which decrease the activity of c-Src include, but arenot limited to, compounds inhibiting the c-Src protein tyrosine kinaseactivity as defined below and to SH2 interaction inhibitors such asthose disclosed in WO97/07131: and WO97/08193;

[0191] compounds inhibiting the c-Src protein tyrosine kinase activityinclude, but are not limited to, compounds belonging to the structureclasses of pyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines,purines, pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines,pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines andpyridopyrimidines, especially pyrido[2,3-d]pyrimidines. Preferably, theterm relates to those compounds disclosed in WO 96/10028, WO 97/28161,WO97/32879 and WO97/49706;

[0192] compounds which decreases the activity of the protein kinase Care especially those staurosporine derivatives disclosed in EP 0 296 110(pharmaceutical preparation described in WO 00/48571) which compoundsare protein kinase C inhibitors;

[0193] further specific compounds that decrease protein kinase activityand which may also be used in combination with the compounds of thepresent invention are Imatinib (Gleevec®/Glivec®), PKC412, Iressa™(ZD1839), PKI166, PTK787, ZD6474, GW2016, CHIR-200131,CEP-7055/CEP-5214, CP-547632 and KRN-633;

[0194] anti-angiogenic compounds having another mechanism of action thandecreasing the protein kinase activity include, but are not limited toe.g. thalidomide (THALOMID), celecoxib (Celebrex), SU5416 and ZD6126.

[0195] The term “gonadorelin agonist” as used herein includes, but isnot limited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX™. Abarelixcan be formulated, eg. as disclosed in U.S. Pat. No. 5,843,901.

[0196] The term “anti-androgens” as used herein includes, but is notlimited to bicalutamide (CASODEX™), which can be formulated, e.g. asdisclosed in U.S. Pat. No. 4,636,505.

[0197] The term “bengamides” relates to bengamides and derivativesthereof having aniproliferative properties.

[0198] The term “bisphosphonates” as used herein includes, but is notlimited to etridonic acid, clodronic acid, tiludronic acid, pamidronicacid, alendronic acid, ibandronic acid, risedronic acid and zoledronicacid. “Etridonic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark DIDRONEL™. “Clodronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONEFOS™. “Tiludronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark SKELID™. “Pamidronicacid” can be administered, eg., in the form as it is marketed, e.g.under the trademark AREDIA™. “Alendronic acid” can be administered,e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™.“Ibandronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark BONDRANAT™. “Risedronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ACTONEL™. “Zoledronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ZOMETA™.

[0199] The term “antiproliferative antibodies” as used herein includes,but is not limited to trastuzumab (Herceptin™), Trastuzumab-DM1,erlotinib (Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®),PRO64553 (anti-CD40) and 2C4 Antibody.

[0200] For the treatment of AML, compounds of formula I can be used incombination with standard leukemia therapies, especially in combinationwith therapies used for the treatment of AML. In particular, compoundsof formula I can be administered in combination with e.g.farnesyltransferase inhibitors and/or other drugs used for the treatmentof AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide,Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

[0201] The structure of the active agents identified by code nos.,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

[0202] The above-mentioned compounds, which can be used in combinationwith a compound of formula I, can be prepared and administered asdescribed in the art such as in the documents cited above.

EXAMPLES

[0203] The following Examples serve to illustrate the invention withoutlimiting its scope.

[0204] Temperatures are measured in degrees Celsius. Unless otherwiseindicated, the reactions take place at RT.

[0205] The R_(f) values which indicate the ratio of the distance movedby each substance to the distance moved by the eluent front aredetermined on silica gel thin-layer plates (Merck, Darmstadt, Germany)by thin-layer chromatography using the respective named solvent systems.

[0206] If not otherwise indicated, the analytical HPLC conditions are asfollows:

[0207] Column: (250×4.6 mm) packed with reversed-phase material C18-Nucleosil (5 μm mean particle size, with silica gel covalentlyderivatized with octadecylsilanes, Macherey & Nagel, Düren, Germany).Detection by UV absorption at 215 nm. The retention times (t_(R)) aregiven in minutes. Flow rate: 1 ml/min.

[0208] Gradient: 20% →100% a) in b) for 14 min+5 min 100% a). a):Acetonitrile+0.05% TFA; b): water+0.05% TFA.

[0209] The short forms and abbreviations used have the followingdefinitions:

[0210] BOC tert-butoxy-carbonyl

[0211] conc. concentrated

[0212] DMF N,N-dimethylformamide

[0213] Elem. anal. elemental analysis

[0214] Et ethyl

[0215] EtOAc ethyl acetate

[0216] MS-ES mass spectroscopy (electron spray)

[0217] h hour(s)

[0218] Me methyl

[0219] MeOH methanol

[0220] min minute(s)

[0221] m.p. melting point

[0222] RT room temperature

[0223] TFA trifluoroacetic acid

[0224] THF tetrahydrofuran (distilled over Na/benzophenone)

[0225] TLC thin-layer chromatography

[0226] t_(R) retention times

Example 1(3-Chloro-4-fluoro-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0227] A mixture of 200 mg (0.5 mmol) crude(3-chloro-4-fluoro-phenyl)-[6.-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminein 15 ml absolute ethanol is treated with 0.8 ml (5 mmol) of a 33%solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) andthen heated under reflux for 1 h. The almost clear solution is cooledand the solvent evaporated. The residue is dissolved in a mixture ofdichloromethane and ethanol (95:5), washed with water, dried over sodiumsulfate and the solvent evaporated. Purification of the crude materialthrough flash chromatography using first dichloromethane/ethanol 95:5plus 1% conc. ammonia and then dichloromethane/ethanol 9:1 plus 1% conc.ammonia gives the title compound; m.p. 274-276° C.; MS-ES⁺: (M+H)⁺=396.

Step 1.1:4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

[0228] 3.6 g (12 mmol)4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) are suspended in 80 ml n-butanol and treated with 3.5 g(24 mmol) 3-chloro-4-fluoro-aniline. The mixture is heated to 145° C.under stirring. After 30 min a clear brown solution is obtained whichturns into a thick suspension after 2 h. After a total of 3 h thereaction mixture is cooled in an ice bath and the product collected byfiltration; m.p.>300° C.; R_(f) (dichloromethane/ethanol 95:5 plus 1%conc. ammonia)=0.29; HPLC t_(R)=11.66 min.

Step 1.2:{4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

[0229] 570 mg (15 mmol) lithium aluminium hydride are suspended in 150ml dry THF at RT.4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester (1.23 g, 3 mmol) are added and the resulting mixture isheated to reflux for 1 h. The mixture is cooled in an ice bath andtreated sequentially with water (0.57 ml), 15% sodium hydroxide solution(0.57 ml) and water (1.71 ml). The solid aluminum complex is removed byfiltration (Hyflo Super Cel®; Fluka, Buchs, Switzerland), the filtratedried over sodium sulfate and the solvent evaporated. The residue wassuspended in water, filtered and dried to give the title compound;m.p.>300° C.; HPLC t_(R)=9.14 min.

Step 1.3:(3-Chloro-4-fluoro-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0230] 184 mg (0.5 mmol){4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolare suspended in 15 ml toluene. Pyridine (44 μl, 0.55 mmol) and thionylchloride (40 μl, 0.55 mmol) are added and the mixture is stirred at RTfor 16 h. A second portion of the same amounts of pyridine and thionylchloride are then added and the mixture stirred for 1 additional hour.The solvent is evaporated and the residue suspended in water containinga small amount of sodium bicarbonate (pH ˜8). After filtration, theproduct was thoroughly washed with water and ether and dried to givecrude title compound; m.p.>300° C.; R_(f) (dichloromethane/ethanol 95:5plus 1% conc. ammonia)=0.42; HPLC t_(R)=11.33 min.

Examples 2-8d:

[0231] The following Examples are synthesized from(3-chloro-4-fluoro-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineusing an analogous procedure described in Example 1: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 2(3-Chloro-4-fluoro-phenyl)-[6-(4- 285-287 424 0.32^(a) 8.54diethylaminomethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]- amine 3(3-Chloro-4-fluoro-phenyl)-{6-[4- 266-268 465 0.42^(b) 7.7(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 4 (3-Chloro-4-fluoro-phenyl)-[6-(4- 268-270 4220.45^(b) 8.4 pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 5(3-Chloro-4-fluoro-phenyl)-{6-[4- 264-266 451 0.33^(b) 7.5(4-methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 6 (3-Chloro-4-fluoro-phenyl)-[6-(4- 267-269 4360.40^(b) 8.66 piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 7 (3-Chloro-4-fluoro-phenyl)-[6-(4-298-300 438 0.21^(a) 8.07 morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 8(3-Chloro-4-fluoro-phenyl)-{6-[4- 261-263 465 0.35^(b) 7.53(3,5-dimethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}- amine 8a(3-Chloro-4-fluoro-phenyl)-(6-{4- 288-290 452 0.43^(c) 7.68[(tetrahydro-pyran-4-ylamino)- methyl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 8b (3-Chloro-4-fluoro-phenyl)-(6-{4- 224-226 4810.3^(d) 7.22 [(2-morpholin-4-yl-ethylamino)-methyl]-phenyl}-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine 8cN-{4-[4-(3-Chloro-4-fluoro- 229-231 467 0.18^(d) 7.41phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-N′,N′-diethyl-ethane-1,2-diamine 8d (3-Chloro-4-fluoro-phenyl)-{6-[4- 282-284410 0.72^(d) 8.14 (isopropylamino-methyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

Example 9{6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine

[0232] A mixture of 10.8 g (30 mmol)[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-aminein 450 ml DMF is treated with 6.8 ml (63 mmol) N-methylpiperazine and20.7 g (150 mmol) anhydrous potassium carbonate and the mixture heatedto 65° C. for 1 hour. The reaction mixture is cooled and the inorganicsalts removed by filtration (Hyflo Super Cel®; Fluka, Buchs,Switzerland). The DMF is evaporated under reduced pressure and theresidue purified through flash chromatography using firstdichloromethane/ethanol 9:1 and then dichloromethane/ethanol 9:1 plus 1%conc. ammonia. Crystallization of the pure fractions from THF (20 ml)and hexanes (80 ml) gives the title compound; m.p. 248-250° C.; MS-ES⁺:(M+H)⁺=427.

Step 9.1:4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

[0233] 1.8 g (6 mmol)4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) are suspended in 40 ml n-butanol and treated with 1.5 ml(12 mmol) (R)-phenethylamine. The mixture is heated to 145° C. understirring. After 3 h a clear brown solution is obtained which is treatedwith a second portion of (R)-phenethylamine (0.75 ml, 6 mmol). Afterstirring for additional 2 h the reaction mixture is cooled in an icebath and the title compound filtered and washed with cold n-butanol andether; m.p. 288-290° C.; MS-ES⁺: (M+H)⁺=387.

Step 9.2:{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

[0234] 570 mg (15 mmol) lithium aluminum hydride are suspended in 150 mldry THF at RT. 1.23 g (3 mmol)4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester are added and the mixture heated to reflux for 1 h. Themixture is cooled in an ice bath and treated sequentially with water(0.57 ml), 15% sodium hydroxide solution (0.57 ml) and water (1.71 ml).The solid aluminum complex is removed by filtration (Hyflo Super Cel®;Fluka, Buchs, Switzerland), the filtrate dried over sodium sulfateevaporated. The residue is suspended in water, filtered and dried togive the title compound; m.p.>300° C.; R_(f) (dichloromethane/ethanol9:1 plus 1% conc. ammonia)=0.43; HPLC t_(R)=8.71 min.

Step 9.3:[6-(4-Chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

[0235] A solution of thionyl chloride (25.7 ml, 0.328 mol) in 180 ml oftoluene is cooled to −10° C. Solid{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol(11.3 g, 0.0328 mol) is added in 8 portions over a range of 1 h. Thetemperature is then increased slowly to 0° C. and the mixture stirredfor 2 h. The cold reaction mixture is filtered and the solid washed withtoluene and ether. The crude product is suspended in water and treatedwith saturated sodium bicarbonate solution until the mixture turnsbasic. The mixture is stirred well for about 10 min and filtered. Thesolid is thoroughly washed with water and dried under reduced pressureto give the title compound; m.p.>320° C.; R_(f) (dichloromethane/ethanol9:1)=0.46; HPLC t_(R)=10.63 min; MS-ES+: (M+H)⁺=363.

Examples 10-16g

[0236] The following Examples are synthesized from[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amineusing an analogous procedure described in Example 9: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 10[6-(4-Diethylaminomethyl- 246-248 400 0.5^(a) 7.96phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-((R)-1-phenyl- ethyl)-amine 11{6-[4-(4-Ethyl-piperazin-1- 245-247 441 0.38^(a) 7.14ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine 12 ((R)-1-Phenyl-ethyl)-[6-(4- 254-256 3980.5^(a) 7.91 pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 13 [6-(4-Dimethylaminomethyl-241-243 427 0.39^(a) 6.35 phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl- ethyl)-amine 14((R)-1-Phenyl-ethyl)-[6-(4- 246-248 412 0.53^(a) 8.1piperidin-1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]- amine 15[6-(4-Morpholin-4-ylmethyl- 263-265 414 0.6^(a) 7.5phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-((R)-1-phenyl- ethyl)-amine 16{6-[4-(3,5-Dimethyl-piperazin-1- 208-210 441 0.3^(a) 7.16ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine 16a (6-{4-[(2-Morpholin-4-yl- 222-224 4570.46^(b) 6.66 ethylamino)-methyl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- ((R)-1-phenyl-ethyl)-amine 16b((R)-1-Phenyl-ethyl)-(6-{4- 253-255 428 0.42^(c) 7.18[(tetrahydro-pyran-4-ylamino)- methyl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 16c N,N-Diethyl-N′-{4-[4-((R)-1- 145-150 4430.55^(b) 6.73 phenyl-ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-ethane-1,2-diamine 16d {6-[4-(tert-Butylamino-methyl)- >300 4000.53^(c) 7.68 phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine 16e {6-[4-(Isopropylamino-methyl)- 266-268 386 0.5^(c) 7.66phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-((R)-1-phenyl- ethyl)-amine16f [6-(4-Ethylaminomethyl-phenyl)- 236-238 372 0.33^(c) 7.417H-pyrrolo[2,3-d]pyrimidin-4-yl]- ((R)-1-phenyl-ethyl)-amine 16g[6-(4-Methylaminomethyl- 234-236 358 0.1^(c) 7.27phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-((R)-1-phenyl- ethyl)-amine

Example 17(4-Benzyloxy-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2.3-d]pyrimidin-4-yl]-amine

[0237] A mixture of 220 mg (0.5 mmol) crude(4-benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminein 15 ml absolute ethanol is treated with 0.8 ml (5 mmol) of a 33%solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) andthen heated under reflux for 1 h. The resulting solution is cooled andthe solvent evaporated. The residue is dissolved in a mixture ofdichloromethane and ethanol (95:5), washed with water, dried over sodiumsulfate and the solvent evaporated. The solid material is then suspendedin ether stirred for 5 min and filtered. Purification of the crudematerial through flash chromatography using dichloromethane/ethanol 9:1plus 1% conc. ammonia gives the title compound; m.p. 272-274° C.;MS-ES⁺: (M+H)⁺=450.

Step 17.1(4-Benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0238] This material is prepared in an analogous procedure as describedin steps 1.1 to 1.3; m.p.>300° C.; HPLC t_(R)=12.19 min; MS-ES⁺:(M+H)⁺=441.

Examples 18-24

[0239] The following Examples are synthesized from(4-benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineusing an analogous procedure described in Example 17: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 18(4-Benzyloxy-phenyl)-{6-[4-(4- 256-258 505 0.28^(a) 8.37methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 19 (4-Benzyloxy-phenyl)-[6-(4- 256-258 4900.5^(b) 9.4 piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 20 (4-Benzyloxy-phenyl)-[6-(4-272-274 492 0.25^(b) 9.03 morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 21 (4-Benzyloxy-phenyl)-[6-(4-271-273 478 0.15^(a) 9.30 diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 22 (4-Benzyloxy-phenyl)-{6-[4-(4-256-258 519 0.6^(b) 8.37 ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine 23(4-Benzyloxy-phenyl)-[6-(4- 265-267 476 0.44^(b) 9.23pyrrolidin-1-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine24 (4-Benzyloxy-phenyl)-{6-[4-(3,5- 269-271 519 0.3^(b) 8.32dimethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

Example 25[6-(3-Dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

[0240] A mixture of 240 mg (0.5 mmol) crude[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-aminein 15 ml ethanol is treated with 0.8 ml (5 mmol) of a 33% solution ofdimethylamine in ethanol (Fluka, Buchs, Switzerland) and then heatedunder reflux for 1 h. The clear solution is cooled and the solventevaporated. The residue is purified with flash chromatography usingdichloromethane/ethanol 95:5 and then dichloromethane/ethanol 9:1 plus1% conc. ammonia to give the title compound; m.p. 108-110° C.; MS-ES⁺:(M+H⁺372.

Step 25.1:{3-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl]-methanol

[0241] This material is prepared in an analogous procedure as describedin steps 9.1 to 9.2; m.p. 217-219° C.; MS-ES⁺: (M+H)⁺⁼345.

Step 25.2:[6-(3-Chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

[0242] A mixture of 688 mg (2 mmol){3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanoland 578 mg (2.2 mmol) triphenylphosphine in 60 ml dichloromethane istreated at 0° C. with 293 mg (2.2 mmol) N-chlorosuccinimide. Afterstirring 1 h at 0° C. all the material has gone into solution. Thesolvent is evaporated and the title compound purified with flashchromatography using dichloromethane/ethanol 95:5 (the title compound iscontaminated with a small amount of triphenylphosphine oxide);

[0243] R_(f) (dichloromethane/ethanol 95:5)=0.35; MS-ES⁺: (M+H)⁺=363.

Examples 26-32

[0244] The following Examples are synthesized from[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amineusing an analogous procedure as described in Example 25: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 26[6-(3-Diethylaminomethyl- 110-113 400 0.6^(a) 8.15phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-((R)-1-phenyl- ethyl)-amine 27{6-[3-(4-Ethyl-piperazin-1- 128-130 441 0.34^(b) 7.3ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine 28 ((R)-1-Phenyl-ethyl)-[6-(3-  90-92 3980.50^(b) 7.97 pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 29 {6-[3-(4-Methyl-piperazin-1-112-115 427 0.27^(b) 7.25 ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}- ((R)-1-phenyl-ethyl)-amine 30((R)-1-Phenyl-ethyl)-[6-(3- 108-110 412 0.6^(b) 8.19piperidin-1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]- amine 31[6-(3-Morpholin-4-ylmethyl- 242-243 414 0.28^(a) 7.8phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-((R)-1-phenyl- ethyl)-amine 32{6-[3-(3,5-Dimethyl-piperazin-1- 128-130 441 0.3^(b) 7.18ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine

Example 33(3-Chloro-4-fluoro-phenyl)-[6-(3-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0245] The title compound is synthesized analogously to Example 1starting with(3-chloro-4-fluoro-phenyl)-[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;m.p.218-220° C.; MS-ES⁺: (M+H)⁺=396.

Step 33.1:(3-Chloro-4-fluoro-phenyl)-[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0246] The title compound is prepared in an analogous procedure asdescribed in steps 1.1 to 1.3; R_(f) (dichloromethane/ethanol 95:5 plus1% conc. ammonia)=0.45; MS-ES⁺: (M+H)⁺=387.

Examples 34-39

[0247] The following Examples are synthesized from(3-chloro-4-fluoro-phenyl)-[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineusing an analogous procedure as described in Example 33: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 34(3-Chloro-4-fluoro-phenyl)-[6- 210-212 424 0.32^(a) 8.76(3-diethylaminomethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4- yl]-amine35 (3-Chloro-4-fluoro-phenyl)-{6- 238-240 465 0.4^(b) 7.7[3-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 36 (3-Chloro-4-fluoro-phenyl)-[6-238-240 422 0.45^(b) 8.44 (3-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine 37(3-Chloro-4-fluoro-phenyl)-{6- 221-223 451 0.33^(b) 7.6[3-(4-methyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}- amine 38 (3-Chloro-4-fluoro-phenyl)-[6-233-235 436 0.45^(b) 8.75 (3-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-amine 39(3-Chloro-4-fluoro-phenyl)-[6- 290-292 438 0.21^(a) 8.15(3-morpholin-4-ylmethy1- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine

Example 40N-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide

[0248] A mixture of 80 mg (0.19 mmol)2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamidein 1.5 ml n-butanol is treated with 47 μl (0.48 mmol) piperidine andthen heated to 100° C. for 2 h. The clear solution is cooled and thesolvent evaporated. The residue is purified with flash chromatographyusing a mixture of ethyl acetate/methanol with increasing concentrationsof methanol starting with 100:2.5 and ending with 10:1. The titlecompound is obtained as a colorless powder; m.p. 194-196° C.; MS-ES⁺:(M+H)⁺=469.

Step 40.1: 2-Amino-5-(4-cyano-phenyl)-1H-pyrrole-3-carboxylic acid ethylester

[0249] A mixture of 42.53 g (0.255 mol) carbamimidoyl-acetic acid ethylester hydrochloride in 70 ml absolute ethanol is treated at 0 to 5° C.with 95.3 ml of a 21% sodium ethoxide solution in ethanol (0.255 mol)and stirred 5 min at 0 to 5° C. 4-Bromoacetyl-benzonitrile (28.6 g,0.128 mol) is then added in portions over 20 min at 0 to 5° C. Stirringis continued at this temperature for 5 min then the ice bath is removedand the yellow suspension is stirred over night at RT. The solid isfiltered off, washed with ethanol and ether and re-suspended in 450 mlactonitrile. The mixture is heated for 5 min under reflux, filteredwhile still hot and then cooled in an ice bath. The title compound iscollected by succion and dried. Flash chromatography(dichloromethane/ethyl acetate mixture) of the mother liquors gives anadditional crop of the title compound as a yellow solid; m.p. 228-229°C.; MS-ES⁺: (M+H)⁺=254.

Step 40.2: 4-(4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile

[0250] A mixture of 36.6 g (0.143 mol)2-amino-5-(4-cyano-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester, 140ml DMF, 305 ml formamide and 14.6 ml 85% formic acid is heated for 16 hat 150° C. The resulting yellow suspension is cooled to 10° C. andfiltered. The solid is washed with methanol (120 ml) and ether (150 ml)and dried. The title compound is obtained as yellowish crystals;m.p.>410° C.; MS-ES⁺: (M+H)⁺=254.

Step 40.3: 4-(4-Chloro-7H-pyrrolo2,3-d]pyrimidin-6-yl)-benzonitrile

[0251] 4-(4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile (2.36g, 0.01 mol) are suspended in 40 ml acetonitril and 4.99 ml (0.02 mol) 4N hydrochloric acid solution in dioxane. After addition of 3.66 ml (0.04mol) phosphorus oxichloride the mixture is heated under reflux for 3days. The solid is filtered off and the mother liquor evaporated. Theresidue and the solid are dissolved in 30 ml DMF at 60° C. and 25 ml ofa conc. sodium bicarbonate solution and 25 ml water are added and theresulting suspension cooled, filtered and the solid washed with water.The title compound is dried at 100° C. for 6 h under reduced pressure;m.p. 296-297° C.; HPLC t_(R)=11.59 min.

Step 40.4:4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzonitrile

[0252] A mixture of 1.27 g (5 mmol)4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile, 1.4 ml (10mol) triethylamine and 0.955 ml (7.5 mmol) R(+)-1-phenyl-ethylamine in25 ml dioxane is heated under reflux for 24 h. A second portion ofR(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) is added and heating iscontinued for 24 h. After addition of a third portion ofR(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) and additional 24 h thereaction mixture is cooled to 10° C. and the title compound filtered offand washed with dioxane. From the mother liquor a second crop isobtained after concentration of the solution; m.p. 333-336° C.; MS-ES⁺:(M+H)⁺=340.

Step 40.5:[6-(4-Aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

[0253] Raney-Nickel (0.1 g) catalyzed hydrogenation of 0.206 g (0.6mmol)4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzonitrilein a mixture of 5% ammonia in methanol (20 ml) and THF (4 ml) for 6 h atatmospheric pressure followed by filtration and evaporation of thesolvent gives the title compound; m.p. 253-256° C.; MS-ES⁺: (M+H)⁺=344.

Step 40.6:2-Chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

[0254] A mixture of 0.21 g (0.6 mmol)[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amineand 94 μl (0.67 mmol) triethylamine in 5 ml dry THF, is treated dropwisewith a solution of chloro-acetyl chloride (51 μl, 0.64 mmol) in 0.5 mlof dry THF at RT. After stirring for 30 min small amounts of insolublematerial is removed by filtration and the filtrate is evaporated. Theresidue is purified by flash chromatography using ethyl acetate/methanol100:2 to 100:4 as eluent. The title compound is obtained as light brownsolid; HPLC t_(R)=9.36 min; MS-ES⁺: (M+H)⁺=420.

Examples 41-45

[0255] The following Examples are synthesized from2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamideusing an analogous procedure as described in Example 40: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 41N-{4-[4-((R)-1-Phenyl- 196-198 455 0.25^(a) 7.92ethylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-2-pyrrolidin-1-yl-acetamide 42 2-Morpholin-4-yl-N-{4-[4-((R)- 199-202 4710.28^(a) 7.78 1-phenyl-ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide 43 2-(4-Methyl-piperazin-1-yl)-N- 150-152 484 0.29^(b)7.45 {4-[4-((R)-1-phenyl- ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}- acetamide 44 2-Dimethylamino-N-{4-[4-((R)-263-266 429 0.21^(a) 7.64 1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- benzyl}-acetamide 452-(4-Ethyl-piperazin-1-yl)-N-{4- 121-124 498 0.26^(b) 7.66[4-((R)-1-phenyl-ethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

Example 46N-{4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide

[0256]2-Chloro-N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(100 mg, 0.225 mmol) in 2 ml n-butanol and 0.12 ml (0.67 mmol) 5.6 Ndimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred andheated to 100° C. for 6 h. The mixture is cooled, filtered and the solidre-suspended in 3 ml hot ethanol. After cooling the title compound iscollected by filtration, washed with ethanol and dried; m.p. 278-282;R_(f) (ethyl acetate/methanol 8:2)=0.14; HPLC t_(R)=8.04 min; MS-ES⁺:(M+H)⁺=453.

Step 46.1: 2-Chloro-N-{4-[4-(3-chloro-4-fluorophenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

[0257] This compound is synthesized using an analogous sequence asdescribed for2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(steps 40.4 to 40.6); m.p. 320-325° C.; R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.39; MS-ES⁺:(M+H)⁺=444.

Examples 47-50

[0258] The following Examples are synthesized from2-chloro-N-{4-[4-(3-chloro4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamideusing an analogous procedure as described in Example 46: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 47N-{4-[4-(3-Chloro-4-fluoro- 245-247 522 0.53^(a) 8.04phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-2-(4-ethyl-piperazin-1-yl)-acetamide 48 N-{4-[4-(3-Chloro-4-fluoro- 272-275495 0.48^(b) 8.19 phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2- morpholin-4-yl-acetamide 49N-{4-[4-(3-Chloro-4-fluoro- 229-232 495 0.48^(a) 8.52phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide 50 N-{4-[4-(3-Chloro-4-fluoro- 246-249 5080.61^(a) 7.93 phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-(4- methyl-piperazin-1-yl)- acetamide

Example 51N-{4-[4-(4-Benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide

[0259]N-{4-[4(4-Benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-chloro-acetamide(0.2 g, 0.4 mmol) in 3 ml n-butanol and 0.215 ml (1.2 mmol) 5.6 Ndimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred andheated to 100° C. for 6 h. After addition of a second portion ofdimethylamine solution (0.3 ml, 1.68 mmol) the mixture is heated for 6more hours. The mixture is then cooled, filtered and the solidre-suspended in 3 ml warm dichloromethane/methanol 2:1. After coolingthe title compound is collected by filtration and purified further withflash chromatography using a gradient of dichloromethane/methanol100:2.5 to 10:1; m.p. 233-235; MS-ES⁺: (M+H)⁺=507.

Step 51.1:N-{4-[4-(4-Benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-chloro-acetamide

[0260] This compound is synthesized using an analogous sequence asdescribed for2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(steps 40.4 to 40.6); R_(f) (dichloromethane/methanol/conc. ammonia90:10:1)=0.40; MS-ES⁺: (M+H)⁺=498.

Examples 52-53

[0261] The following Examples are synthesized fromN-{4-[4-(4-benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-chloro-acetamideusing an analogous procedure as described in Example 51: Example m.p.MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min] 52N-{4-[4-(4-Benzyloxy- 232-234 562 0.18^(a) 8.69phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-2-(4-methyl-piperazin-1-yl)-acetamide 53 N-{4-[4-(4-Benzyloxy- 246-248 5470.42^(b) 9.31 phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide

Example 54N-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl-benzyl}-3-piperidin-1-yl-propionamide

[0262] Under an atmosphere of nitrogen a mixture of 0.0865 g (0.55 mmol)3-piperidin-1-yl-propionic acid and 0.117 ml (0.68 mmol)N,N-diisopropylethylamine in DMF (5 ml) is treated at RT and over aperiod of 5 min with a solution of 0.163 g (0.55 mmol)O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium-tetrafluroborate(TPTU, Fluka, Buchs, Switzerland) in 2 ml DMF. After stirring for 5 minthe resulting solution is added slowly (1.5 h) at RT to 0.172 g (0.5mmol)[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(step 40.5) in 3 ml DMF. The reaction mixture is allowed to stand overnight after which the DMF is evaporated under reduced pressure. Theresidue is purified by flash chromatography using gradients of firstdichloromethane/methanol 100:2.5 to 10:1 and then mixtures ofdichloromethane/methanol/conc. ammonia 90:10:0.5 to 40:10:1. The titlecompound is obtained as yellowish solid; m.p. 140° C.; MS-ES⁺:(M+H)⁺=483.

[0263] As a second product of this reactionN-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acrylamideis obtained; m.p. 249-250° C.; MS-ES⁺: (M+H)⁺=398.

Examples 55-57

[0264] The following Examples are synthesized from[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(step 40.5) using an analogous procedure as described in Example 54:Example m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 55 3-Diethylamino-N-{4-[4-((R)-1- 175-177 471 0.19^(a) 8.11phenyl-ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-propionamide 56 4-Dimethylamino-N-{4-[4-((R)- 195-203 457 0.04^(a) 7.761-phenyl-ethylamino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-butyramide 57 Pyridine-2-carboxylic acid 4-[4- 221-223 4490.51^(a) 10.16 ((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- benzylamide

Example 58N-{4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl-benzyl{-3-diethylamino-propionamide

[0265] The title compound is synthesized from[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-chloro-4-fluoro-phenyl)-amineusing an analogous procedure as described in Example 54. In this caseactivation of the carboxylic acid is done with(benzotriazole-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluoroborate(BOP, Fluka, Buchs, Switzerland) and N-methylmorpholin; m.p. 229-232;HPLC t_(R)=8.52 min; MS-ES⁺: (M+H)⁺=495.

Step 58.1:[6-(4-Aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-chloro-4-fluoro-phenyl)-amine

[0266] The title compound is synthesized using an analogous procedure asdescribed in steps 40.4 to 40.5; m.p. 350-351; MS-ES⁺: (M+H)⁺=368.

Examples 59-61

[0267] The following Examples are synthesized from[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-chloro-4-fluoro-phenyl)-amine(step 58.1) using an analogous procedure as described in Example 58:Example m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 59 Pyridine-2-carboxylic acid 4-[4- 340-342 473 — 10.62(3-chloro-4-fluoro-phenylamino)- 7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzylamide 60 N-{4-[4-(3-Chloro-4-fluoro- 272-273 481 0.31^(a) 8.15phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-4-dimethylamino-butyramide 61 N-{4-[4-(3-Chloro-4-fluoro- 230-235 5070.76^(a) 8.66 phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-3-piperidin-1-yl-propionamide

Example 622-Dimethylamino-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-benzyl]-acetamide

[0268] A mixture of 210 mg (0.5 mmol)2-chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamidein 3 ml dry dioxane is treated with 268 μl (1.5 mmol) of a 5.6 Ndimethylamine solution in ethanol (Fluka, Buchs, Switzerland) and thenheated to 100° C. for 6 h. The clear yellow solution is cooled and thesolvent evaporated. The residue is purified by flash chromatographyusing a mixture of dichloromethane/methanol with gradually increasingconcentrations of methanol starting with 100:2.5 and ending with 100:5and then switching to dichloromethane/methanol/conc. ammonia startingwith 100:5:0.25 and ending with 100:10:0.5. The title compound isobtained as a colorless foam; R_(f) (dichloromethane/methanol/conc.ammonia 90:10:1)=0.41; MS-ES⁺: (M+H)⁺=429.

Step 62.1:2-Chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

[0269] The title compound is synthesized using an analogous procedure asdescribed in steps 40.1 to 40.6; m.p. 300-310 (decomposition); R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.54; MS-ES⁺:(M+H)⁺=420.

Example 632-(4-Methyl-piperazin-1-yl)-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

[0270] The title compound is obtained as a tan resin using an analogousprocedure as described in Example 62; R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1) =0.20; HPLC t_(R)=7.77min; MS-ES⁺: (M+H)⁺=484.

Example 64N-{3-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide

[0271]2-Chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(120 mg, 0.222 mmol) in 2 ml dioxane and 0.145 ml (0.81 mmol) 5.6 Ndimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred andheated to 100° C. for 4.5 h. The mixture is cooled and the solventevaporated. The residue is shaken with THF (5 ml), dichloromethane (3ml), methanol (2 ml) and saturated sodium bicarbonate (2 ml). The twoclear layers are separated and the organic phase is treated with 1 gsilica gel. The solution containing the silica gel is evaporated and thesolid put on top of a flash chromatography column containing 33 g ofsilica gel. The column is eluted using a mixture ofdichloromethane/methanol with gradually increasing concentrations ofmethanol starting with 100:2.5 and ending with 100:5 and then switchingto dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 andending with 100:10:0.5. The title compound is obtained as colorlesscrystals; m.p. 272-273 ° C.; MS-ES⁺: (M+H)⁺=453.

Step 64.1:2-Chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

[0272] The title compound is synthesized using an analogous procedure asdescribed in steps 40.1 to 40.6; R_(f) (dichloromethane/methanol/conc.ammonia 90:10:1)=0.47; HPLC t_(R)=9.98 min; MS-ES⁺: (M+H)⁺=444.

Examples 65-66

[0273] The following Examples are synthesized from2-chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(step 64.1) using an analogous procedure as described in Example 64:Example m.p. MS-ES⁺: TLC^(a) HPLC Number Name [° C.] (M + H)⁺ R_(f)t_(R) [min] 65 N-{3-[4-(3-Chloro-4-fluoro- 214—214 508 0.21 8.08phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-2-(4-methyl-piperazin-1-yl)-acetamide 66 N-{3-[4-(3-Chloro-4-fluoro- 252-254493 0.53 8.65 phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide

Examples 67-78

[0274] The following Examples are synthesized using an analogousprocedure as described in Example 1. However, a modified protocol isapplied for the preparation of the intermediates: Instead of reducingthe ethyl-ester with lithium aluminum hydride in THF (as described instep 1.2), the 4-hydroxymethyl derivatives are prepared by reductionwith diisobutyl-aluminium hydride in a 1:1 mixture of dichloromethaneand dioxane at ambient temperature (Examples 67-72 and 76-78). Forpreparing the intermediates of Examples 73-75, reduction of4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl esterwith diisobutyl-aluminium hydride in THF at ambient temperature yields[4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol (see step108.3). Substitution of the chlorine by 2-methoxy-5-amino-phenol asdescribed in step 1.1 then gives5-[6-(4-hydroxymethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methoxy-phenol.Example m.p. MS-ES⁺: TLC HPLC^(a) Number Name [° C.] (M + H)⁺ R_(f)t_(R) [min] 67 2-Methyl-5-{6-[3-(4-methyl- 256-258 429 0.14^(b) 6.8piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol 68 5-[6-(3-Dimethylaminomethyl- 258-260 374 0.21^(b) 7.2phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino]-2-methyl- phenol 692-Methoxy-5-{6-[3-(4-methyl- 251-252 445 0.16^(b) 6.1piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol 70 5-[6-(3-Dimethylaminomethyl- 250-251 390 0.17^(b) 6.8phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino]-2- methoxy-phenol 715-[6-(4-Dimethylaminomethyl- 374 0.31^(b) 7.2 phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methyl- phenol 722-Methyl-5-{6-[4-(4-methyl- >300 429 6.9 piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino}-phenol 735-[6-(4-Dimethylaminomethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2- methoxy-phenol 74 2-Methoxy-5-{6-[4-(4-methyl-445 0.19^(d) 6.3 piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino}-phenol 752-Methoxy-5-[6-(4-morpholin-4- ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-phenol 76 [(R)-1-(4-Chloro-phenyl)-ethyl]-273-274 406 0.32^(b) 9.1 [6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine 77[(R)-1-(4-Chloro-phenyl)-ethyl]- 232-233 461 0.31^(b) 8.6{6-[4-(4-methyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}- amine 78 [(R)-1-(4-Chloro-phenyl)-ethyl]-448 0.16^(c) 9.2 [6-(4-morpholin-4-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

Example 79(3-Chloro-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminehydrochloride

[0275] Lithium aluminum hydride (72 mg,1.9 mmol) is suspended in dry THF(12 ml) under a nitrogen atmosphere. Solid4-[4-(3-chloro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-N,N-dimethyl-benzamide(described in WO 97/02266, 140 mg, 0.37 mmol) is added and the mixtureheated to 60° C. for 1 h. The reaction mixture is then hydrolized at 0°C. by sequential addition of water (0.072 ml), 15% sodium hydroxide(0.072 ml) and water (0.21 ml). The precipitate is removed by filtrationand the filtrate concentrated on a rotary evaporator. The yellowcrystalline residue is suspended in methanol, filtered, suspended intoluene, filtered, suspended in methanol again and filtered to give thefree base of the title compound [R_(f) (dichloromethane/methanol 9:1plus 1 drop of conc. ammonia)=0.36]. This is suspended in methanol (2ml) and treated with 1 N hydrochloric acid (0.2 ml). The suspension isstirred well and filtered. The crystals are triturated in methanol/water9:1 and filtered again to give the title compound; m.p. 280-283° C.;MS-ES⁺: (M+H)⁺=378.

Examples 80-81

[0276] The following Examples are synthesized from the correspondingamides (WO 97/02266) using an analogous procedure as described inExample 79: Example m.p. MS-ES⁺: TLC^(a) HPLC Number Name [° C.] (M +H)⁺ R_(f) t_(R) [min] 80 (3-Chloro-phenyl)-{6-[4-(4- 227-229 433 0.356.74 methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine dihydrochloride 81 (3-Chloro-phenyl)-[6-(4-278-280 420 0.49 7.25 morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine hydrochloride

Example 822-((2-Hydroxy-ethyl)-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2.3-d]pyrimidin-6-yl]-benzyl}-amino)-ethanol

[0277][6-(4-Aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(step 40.5, 0.5 g, 1.46 mmol) is dissolved in THF (7.5 ml) and water(0.75 ml) and cooled to −10° C. A stream of ethylene oxide is thenpassed through the solution for about 40 min (amount of ethylene oxideabsorbed 5 to 6 g). The flask is sealed and the mixture stirred at 0° C.for 30 min and then at 50° C. for 16 h. The clear yellow solution iscooled and the solvents evaporated. The residue is purified by flashchromatography on 34 g of silica gel. The column is eluted using amixture of dichloromethane/methanol with gradually increasingconcentrations of methanol starting with 100:1.25 and ending with100:2.5 and then switching to dichloromethane/methanol/conc. ammoniastarting with 100:2.5:0.125 and ending with 100:10:0.5. Fractionscontaining the title compound were pooled and concentrated on a rotaryevaporator. The residue is taken up in a small amount of dichloromethaneand the resulting solid collected by filtration; m.p. 194-197° C.; R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.21; MS-ES⁺:(M+H)⁺=432.

Example 83(3-Chloro-benzyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

[0278](3-Chloro-benzyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-(d]pyrimidin-4-yl]-amine(150 mg, 0.35 mmol) is suspended in 5 ml dioxane and treated withN-ethyl-piperazine. The mixture is heated to 90° C. for 7 h. The solventis evaporated and the residue is purified by flash chromatography on 34g of silica gel. The column is eluted using a mixture ofdichloromethane/methanol with gradually increasing concentrations ofmethanol starting with 100:1.25 and ending with 100:5 and then switchingto dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 andending with 100:10:0.5. Fractions containing the title compound werepooled and concentrated on a rotary evaporator to give the titlecompound; m.p. 241-243° C.; MS-ES⁺: (M+H)⁺=461.

Step 83.1:4-[4-(3-Chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

[0279] This compound is synthesized following an analogous procedure asdescribed in Example 1, step 1.1 starting from4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) and 3-chloro-benzylamine; m.p. 305-306° C.; MS-ES⁺:(M+H)⁺=407.

Step 83.2:{4-[4-(3-Chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

[0280] 2.236 g (0.059 mol) lithium aluminum hydride are suspended in 600ml dry THF at RT.4-[4-(3-Chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester (4.8 g, 0.0118 mol) is added in portions over 5 min andthe resulting mixture is heated to 60° C. for 1 h. The mixture is cooledin an ice bath to about 10° C. and treated sequentially with THF/water1:1 (2.24 ml), 15% sodium hydroxide solution (4.48 ml) and water (6.72ml). The solid aluminum complex is removed by filtration (Hyflo SuperCel®; Fluka, Buchs, Switzerland) and washed thoroughly with THF. Thefiltrate is concentrated to about 50 ml and the resulting suspensiontreated with water/ethanol 9:1 (50 ml). After stirring for 10 min thecrystals were collected by filtration and dried under reduced pressureto give the title compound; m.p. 296-298° C.; MS-ES⁺: (M+H)⁺=365.

Step 83.3:(3-Chloro-benzyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0281] A solution of 0.79 ml (10 mmol) thionylchloride in 5.5 ml oftoluene is cooled to −10° C. Solid{4-[4-(3-chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolis added and the suspension stirred at 0° C. for 2 h and then at RT for17 h. The solid is filtered off, washed with toluene and suspended inwater (3 ml). The mixture is treated with saturated sodium bicarbonatesolution (3 ml) and stirred for 10 min. The crystals are collected byfiltration washed with water, a small amount of ethanol and ether anddried to give the title compound; m.p. decomposition ˜300° C.; R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.61; MS-ES⁺:(M+H)⁺=383.

Examples 84-107i

[0282] The following Examples are synthesized using an analogousprocedure as described in Example 83: Example m.p. MS-ES⁺: TLC HPLCNumber Name [° C.] (M + H)⁺ R_(f) t_(R) [min]  84(3-Chloro-benzyl)-[6-(4- 219-222 393 — 7.46 dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  85 (3-Chloro-benzyl)-[6-(4-234-235 432 0.44^(a) 7.95 piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  86 (3-Chloro-benzyl)-[6-(4-  253-254.5 434 — 7.55 morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  87 (3-Chloro-benzyl)-[6-(4-231-233 420 0.35^(a) 7.86 diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  88 (3-Chloro-benzyl)-[6-(4-222-225 418 0.32^(a) 7.77 pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  89 (3-Chloro-benzyl)-{6-[4-(4-235-237 447 0.34^(a) 6.99 methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine  90(2-Chloro-benzyl)-[6-(4- 256-258 392 0.30^(a) 7.65dimethylaminomethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  91(2-Chloro-benzyl)-{6-[4-(4-ethyl- 255-256 461 0.23^(a) 7.37piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl}- amine 92 (2-Chloro-benzyl)-[6-(4- 262-264 432 0.54^(a) 7.77piperidin-1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]- amine 93 (2-Chloro-benzyl)-[6-(4- 276-279 434 0.42 7.39morpholin-4-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 94 (2-Chloro-benzyl)-{6-[4-(4- 267-269 447 0.37^(a) 6.80methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine  95 (2-Chloro-benzyl)-[6-(4- 264-265 4180.33^(a) 7.59 pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  96 (2-Chloro-benzyl)-[6-(4-257-258 420 0.42^(a) 7.69 diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  97 (2,5-Dichloro-benzyl)-{6-[4-(4-249-251 495 0.30^(a) 7.44 ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine  98(2,5-Dichloro-benzyl)-[6-(4- 254-257 426 0.30^(a) 7.91dimethylaminomethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine  99(2,5-Dichloro-benzyl)-[6-(4- 272-274 468 0.42^(b) 7.97morpholin-4-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine100 (2,5-Dichloro-benzyl)-[6-(4- 258-260 466 — 8.44piperidin-1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]- amine101 (2,5-Dichloro-benzyl)-[6-(4- 255-257 454 0.50^(c) 8.26diethylaminomethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]- amine 102(2,5-Dichloro-benzyl)-{6-[4-(4- 244-246 481 0.37^(c) 7.43methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 103 (2,5-Dichloro-benzyl)-[6-(4- 266-268 4520.48^(a) 8.20 pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine 104 [6-(4-Dimethylaminomethyl-227-229 388 0.40^(d) 6.91 phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-methoxy- benzyl)-amine 105[6-(4-Diethylaminomethyl- 230-232 416 0.57^(d) 7.36phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-(3-methoxy- benzyl)-amine 106(3-Methoxy-benzyl)-[6-(4- 220-222 414 0.50^(d) 7.29pyrrolidin-1-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine107 (3-Methoxy-benzyl)-[6-(4- 227-229 428 0.30^(e) 7.48piperidin-1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]- amine107a (3-Methoxy-benzyl)-[6-(4- 263-265 430 0.42^(f) 7.02morpholin-4-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine107b (3-Methoxy-benzyl)-{6-[4-(4- 225-227 443 0.12^(f) 6.43methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 107c {6-[4-(4-Ethyl-piperazin-1- 231-233 4570.45^(f) 6.66 ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-(3-methoxy-benzyl)-amine 107d (3-Methyl-benzyl)-[6-(4- 246-248 412 0.46^(f)7.88 piperidin-1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-amine 107e (3-Methyl-benzyl)-[6-(4- 259-261 414 0.37^(f) 7.74morpholin-4-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine107f [6-(4-Dimethylaminomethyl- 230-232 372 0.58^(d) 7.23phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-(3-methyl- benzyl)-amine 107g[6-(4-Diethylaminomethyl- 241-243 400 0.6^(d) 7.71phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-(3-methyl- benzyl)-amine 107h(3-Methyl-benzyl)-[6-(4- 241-243 398 0.5^(d) 7.63pyrrolidin-1-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine107i (3-Methyl-benzyl)-{6-[4-(4- 244-246 427 0.5^(d) 6.87methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 107j {6-[4-(4-Ethyl-piperazin-1- 250-252 4410.4^(d) 6.9 ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-(3-methyl-benzyl)-amine

Example 108Benzo[1,3]dioxol-5-yl-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

[0283] A mixture of 200 mg (0.53 mmol)benzo[1,3]dioxol-5-yl-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine,0.59 ml (5.3 mmol) 1-methyl-piperazine and a trace of Nal in 15 mlethanol is stirred for 4 h at 65° C. and 2 h at 80° C. underN₂-atmosphere. The orange solution is concentrated under vacuum and theresidue resolved with ethyl acetate and NaHCO₃-solution. The aqueouslayer is separated off and extracted twice with ethyl acetate. Theorganic phases are washed with water and brine, dried (MgSO₄) andpartially concentrated. Then the crystallized title compound can befiltered off; MS-ES⁺: (M+H)⁺=443; HPLC (conditions see Examples 67-78)t_(R)=7.1 min.

Step 108.1:14-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol

[0284] To a suspension of 30.0 g (100 mmol)4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) in 450 ml dry THF at 10° C. under N₂-atmosphere, 500 mldiisobutyl-aluminium hydride (1 M in THF) were added dropwise. Theresulting clear solution is stirred for 1 h and then diluted with 2.1 1of dry THF. Then 98 ml of ethyl acetate are added, followed after 15 minby 45 ml of water and after 1 h by 22.5 ml of 4 N sodium hydroxide.After 1 h stirring, 200 g of Na₂SO₄ are added and stirring is continuedfor another hour. The mixture is filtered through Celite (Fluka, Buchs,Switzerland), the residue washed with THF and discarded. Concentrationof the filtrate to a volume of ≈0.1 l, addition of 0.3 l ofdichloromethane and filtration yields the title compound; Analysis forC₁₃H₁₀ClN₃O: calc. C 60.13%, H 3.88%, N 16.18% ,Cl 13.65%; found C60.23%, H 4.03%, N 16.51%, Cl 13.28%.

Step 108.2:{4-[4-(Benzo[1,3]dioxol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

[0285] A mixture of 1.5 g (5.8 mmol) of[4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol and 1.58g (11.5 mmol) 3,4-methylendioxy-aniline in 30 ml n-butanol is stirredfor 16 h at 115° C. under N₂-atmosphere. After cooling to ambienttemperature, the title compound can be filtered off and washed withn-butanol; MS-ES⁺: (M+H)⁺=361; HPLC (conditions see Examples 67-78)t_(R)=8.7 min.

Step 108.3:Benzo[1,3dioxol-5-yl-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0286] To a suspension of 1.83 g of{4-[4-(benzo[1,3]dioxol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-6-yl]-phenyl}-methanolin 56 ml of dioxane/acetonitrile 1:1 under N₂-atmosphere, 3.1 ml ofthionylchloride are added. After 16 h stirring, the suspension isdiluted with ethyl acetate and NaHCO₃-solution. The aqueous layer isseparated off and extracted twice with ethyl acetate. The organic phasesare washed with water and brine, dried (MgSO₄) and concentrated to yieldthe title compound; MS-ES⁺: (M+H)⁺=379; HPLC (conditions see Examples67-78) t_(R)=11.4 min.

Examples 108a -114

[0287] The following Examples are synthesized using an analogousprocedure as described in Example 108: Example m.p. MS-ES⁺: TLC HPLC^(a)Number Name [° C.] (M + H)⁺ R_(f) t_(R) [min]  108aBenzo[1,3]dioxol-5-yl-{6-[4-(4- 457 0.32^(c) 7.3ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 109 Benzo[1,3]dioxol-5-yl-[6-(4- 388 0.08^(b)7.6 dimethylaminomethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine110 Benzo[1,3]dioxol-5-yl-[6-(4- 430 0.16^(b) 7.7morpholin-4-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine111 (6-Methoxy-pyridin-3-yl)-[6-(4- 263-264 417 0.78^(c) 7.2morpholin-4-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]- amine112 (6-Methoxy-pyridin-3-yl)-{6-[4- 241-242 430 0.07^(b) 6.9(4-methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 113 (6-Methoxy-pyridin-3-yl)-{6-[4- 375 0.49^(c)7.0 (dimethylamino-methyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 114 (6-Methoxy-pyridin-3-yl)-{6-[4- 444 0.41^(c) 6.8(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

Example 1155-[6-(4-Morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1H-pyridin-2-one

[0288] To 84 mg (0.20 mmol) of(6-methoxy-pyridin-3-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-[2,3-d]pyrimidin-4-yl]-amineand 10 ml chloroform in an ampoule under N₂-atmosphere, 0.1 ml (0.73mmol) Me₃Sil is added. After stirring for 6 h at 70° C., diluted NaHCO₃solution and EtOAc is added to the suspension at RT. Stirring,filtration and washing with water yields the title compound; TLC(THF/methanol/conc. ammonia 90:10:1) R_(f)=0.23; MS-ES⁺: (M+H)⁺=403;HPLC (conditions see Examples 67-78) t_(R)=4.7 min.

Examples 116-118

[0289] The following Examples are synthesized using an analogousprocedure as described in Example 115 (eventually after purificationwith chromatography on SiO₂ or reversed phase medium pressure liquidchromatography: Nucleosil C₁₈, CH₃CN/H₂O+TFA): Example MS-ES⁺: TLCHPLC^(a) Number Name (M + H)⁺ R_(f) t_(R) [min] 1165-[6-(4-Dimethylaminomethyl- 361 0.09^(d) 9.2^(b)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino]-1H- pyridin-2-one 1175-{6-[4-(4-Methyl-piperazin-1- 416 9.0^(c) ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino}-1H-pyridin-2-one 1185-{6-[4-(4-Ethyl-piperazin-1- 430 9.1^(c) ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino}-1H-pyridin-2-one

Example 119(6-Methoxy-pyridin-3-ylmethyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

[0290](6-Methoxy-pyridin-3-ylmethyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine(400 mg, 1.05 mMol), 1.34 ml N-ethyl-piperazine and a trace of Nal isstirred for 2.5 h in 30 ml boiling ethanol. The solvent is evaporatedand the residue is re-dissolved in EtOAc and diluted NaHCO₃-solution.The separated aqueous layer is re-extracted with EtOAc and the organicphases are washed with water and brine, dried (Na₂SO₄) and partiallyconcentrated in vacuuo. The title compound crystallizes and can befiltered off; MS-ES⁺: (M+H)⁺=458; elemental analysis for C, H and Nwithin 0.5% of calculated value.

Step 119.1:4-[4-(6-Methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

[0291] A mixture of 5.0 g (16.6 mMol)4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) and 2.52 g (18 mMol) of 6-methoxy-pyridin-3-ylmethylamine(CAS: 262295-96-5; prepared from 6-methoxy-nicotin-nitrile byhydrogenation in the presence of Raney-Nickel in methanol containingNH₃) in 3.5 ml (25 mMol) of Et₃N and 100 ml n-butanol is heated for 8 hto 140° C. Then additional 0.69 g of 6-methoxy-pyridin-3-ylmethylamineand 1.2 ml of Et₃N are added. Heating is continued for 6 h and the hotsuspension filtrated and the residue washed with n-butanol and hexane togive the title compound; m.p. 305° C.; elemental analysis for C, H and NWithin 0.5% of calculated value.

Step 119.2:{4-[4-(6-Methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl-methanol

[0292] 5.0 g (12 mMol) of4-[4-(6-methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester in 200 ml of THF is cooled to −10° C. Then 80 ml of a 1N solution of di-isobutyl-aluminium hydride in THF are added dropwise.After stirring for 3 h at RT, 200 ml of THF and 100 ml of EtOAc areadded, followed by 10 ml of a 10%-solution of NH₄Cl in water. After 30min vigorous stirring, 20 g of Na₂SO₄ are added, then the mixture isfiltered through Celite. Concentration of the filtrate, stirring inmethanol and filtration gives the title compound; MS-ES⁺: (M+H)⁺=362.

Step 119.3:(6-Methoxy-pyridin-3-ylmethyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0293] A suspension of 3.28 g (9.1 mMol) of{4-[4-(6-methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolin 40 ml of acetonitrile, 40 ml of dioxane and 4 ml of SOCl₂ is stirredfor 1 h at RT. The mixture is dissolved in EtOAc and NaHCO₃-solution,the aqueous layer separated off and extracted with EtOAc. The organiclayers are washed with NaHCO₃-solution, water and brine, dried (Na₂SO₄)and partially concentrated. The crystallized title compound can befiltered off; elemental analysis for C, H and N within 0.4% ofcalculated value.

Examples 120-125

[0294] The following Examples are synthesized analogously: Example m.p.MS-ES⁺: HPLC ^(a) Elem. Number Name [° C.] (M + H)⁺ t_(R) [min] anal.^(b) 120 (6-Methoxy-pyridin-3-ylmethyl)- 431 7.2 CHN{6-[4-(morpholin-4-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 121 (6-Methoxy-pyridin-3-ylmethyl)- 389 7.1 CHN{6-[4-(dimethylamino-methyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 122 (2-Methoxy-pyridin-4-ylmethyl)- 210-212 4586.6 {6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}- amine^(c) 123(2-Methoxy-pyridin-4-ylmethyl)- 431 7.0 {6-[4-(morpholin-4-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine ^(c) 124(2-Methoxy-pyridin-4-ylmethyl)- 210-211 389 6.8 CHN{6-[4-(dimethylamino-methyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine ^(c) 125 (2-Methoxy-pyridin-4-ylmethyl)- 211-212444 6.3 CHN {6-[4-(4-methyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}- amine^(c)

Examples 126-132

[0295] Cleavage of the methylether of the above compounds analogously toExample 115 gives: Example m.p. MS-ES⁺: HPLC ^(a) Elem. Number Name [°C.] (M + H)⁺ t_(R) [min] anal. ^(d) 126 5-({6-[4-(4-Ethyl-piperazin-1-444 9.4 ^(b) ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2- one 127 5-({6-[(4-(Dimethylamino- 375 9.6^(b) CHN methyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one 128 5-({6-[4-(4-Morpholin-ylmethyl)- 417 9.7 ^(b) CHNphenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino}-methyl)- 1H-pyridin-2-one129 4-({6-[4-(4-Ethyl-piperazin-1- 291-292 444 9.4 ^(b)ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2- one 130 4-({6-[4-(4-Morpholin-ylmethyl)-417 5.7 ^(c) CHN phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one 131 4-({6-[(4-(Dimethylamino- 330-332 375 5.6 ^(c) CHNmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one 132 4-({6-[4-(4-Methyl-piperazin-1- 5.0 ^(c) CHNylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2- one

Example 133(2-Methoxy-pyridin-4-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0296] 330 mg (0.90 mMol)(2-Methoxy-pyridin-4-yl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine,0.81 ml morpholine and a trace of Nal is stirred for 2 h in 20 mlboiling ethanol. A clear solution is formed from which upon cooling toRT the title compound crystallizes out and can be filtered off; TLC(CH₂Cl₂/methanol 9:1) R_(f)=0.33; MS-ES⁺: (M+H)⁺=417.

Step 133.1:{4-[4-(2-Methoxy-pyridin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

[0297] To 4.16 g (16 mMol) of[4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol (see Step108.3) and 1.99 g (16 mMol) of 2-methoxy-pyridin-4-ylamine [see Rec.Trav. Chim. (1955) 74, 1160; prepared from2-methoxy-4-nitro-pyridine-1-oxide by hydrogenation in the presence ofRaney-Nickel in methanol/THF] in 90 ml degassed DMF under N₂-atmosphere,996 mg of R(+)-BINAP[R(+)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthalin); 1.6 mMol], 414 mgPd₂(dba)₃CHCl₃ [tris(dibenzylideneacetone)dipalladium (0) chloroformcomplex; 0.40 mMol] and 3.08 g (32 mMol) of sodium-tert-butylate aresubsequently added. The red solution is stirred at 70° C. over night andthen poured into a mixture of 0.5 l of EtOAc and 1 l buffer (7.8 g ofNaH₂PO₄.2H₂O, 5 g of Na₂HPO₄.2H₂O in 1 l H₂O). After stirring for 1 h,the title compound is filtered off and washed with water and EtOAc; HPLC(conditions see Examples 67-78) t_(R)=8.2 min; MS-ES⁺: (M+H)⁺=348.

Step 133.2:(2-Methoxy-pyridin-4-yl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0298] At 0° C., a suspension of 1.23 g (3.5 mMol) of{4-[4-(2-methoxy-pyridin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol in 18 ml ofacetonitrile, 18 ml of dioxane and 1.5 ml of SOCl₂ is prepared at 0° C.and then stirred for 4.5 h at RT. The mixture is diluted with 0.2 l ofEtOAc and 0.1 l of saturated NaHCO₃-solution, stirred and the titlecompound filtered off; MS-ES⁺: (M+H)⁺=366. More product can be obtainedby extraction of the filtrate.

Examples 134-140

[0299] The following Examples are synthesized by preparing thecorresponding methoxy pyridines analogously to Example 133 followed byde-methylation to the corresponding pyridones as described in Example115: Example MS-ES⁺: HPLC ^(a) Elem. TLC Number Name (M + H)⁺ t_(R)[min] anal. ^(b) R_(f) 134 4-[6-(4-Morpholin-4-ylmethyl- 403 7.3 0.24^(c) phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino]-1H- pyridin-2-one135 (2-Methoxy-pyridin-4-yl)-{6-[4- 430 7.2 0.35 ^(c)(4-methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 136 4-{6-[4-(4-Methyl-piperazin-1- 416 7.0 0.08^(c) ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-1H-pyridin-2-one 137 (2-Methoxy-pyridin-4-yl)-{6-[4- 444 7.70.48 ^(d) (4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 138 4-{6-[4-(4-Ethyl-piperazin-1- 430 7.2 0.10^(c) ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-1H-pyridin-2-one 139 [6-(4-Dimethylaminomethyl- 375 7.2 CHN0.47 ^(d) phenyl)-7H-pyrrolo[2,3-d]pyri-midin-4-yl]-(2-methoxy-pyridin-4- yl)-amine 1404-[6-(4-Dimethylaminomethyl- 361 7.2 0.08 ^(c) phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1H- pyridin-2-one

Example 1416-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl[-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidine

[0300] 1.56 ml of diisobutyl-aluminium hydride (1 M in THF) are added toa solution of 130 mg (0.26 mMol) of(4-ethyl-piperazin-1-yl)-{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanonein 13 ml of THF at −15° C. under a N₂-atmosphere. After 3 h, 4 ml ofEtOAc are added to the solution, followed by 0.2 ml of a saturatedsolution of NH₄Cl in water. After adding solid Na₂SO₄, the reactionmixture is filtered through Celite. The filtrate is concentratedtogether with 3 g of SiO₂. The resulting powder is put on top of achromatography column (SiO₂) and then eluted with EtOAc/methanol 4:1 andfinally EtOAc/methanol/NEt₃ 80:20:1, yielding the title compound; HPLC(conditions see Examples 67-78) t_(R)=10.5 min; MS-ES⁺: (M+H)⁺=485.

Step 141.1:4-[4-Chloro-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

[0301] A suspension of 3.0 g (10 mMol) of4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266), 2.4 g (17 mMol) of K₂CO₃, 0.32 g (1 mMol) oftetrabutyl-ammoniumbromide and 2.0 ml (15 mMol) of4-methoxy-benzylchloride in 25 ml of 2-butanone is stirred for 18 h at80° C. Then the suspension is filtered, the residue washed with2-butanone and discarded. The filtrate is diluted with EtOAc and water,the aqueous layer separated off and extracted twice with EtOAc. Theorganic layers are washed with water and brine, dried (Na₂SO₄) andconcentrated after adding 13 g of SiO₂. The resulting powder is put ontop of a chromatography column (SiO₂) and then eluted with hexane/EtOAc2:1.4-[4-Chloro-7-(4-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester [TLC (hexane/EtOAc 2:1) R_(f)=0.40; MS-ES⁺: (M+H)⁺=422]is eluated first, followed by the title compound; TLC (hexane/EtOAc 2:1)R_(f)=0.23; MS-ES⁺: (M+H)⁺=422.

Step 141.2:4-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

[0302] A mixture of 3.96 g (9.4 mMol) of4-[4-chloro-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester, 2.14 g (13 mMol) of4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212; Ex.237) and 2.44 (17.7 mMol) of K₂CO₃ in 90 ml of DMF is heated for 9 h at95° C. The reaction mixture is concentrated in vacuuo, the residuedissolved in EtOAc and water, the aqueous layer separated off andextracted twice with EtOAc. The organic layers are washed with water andbrine, dried (Na₂SO₄) and concentrated. Column chromatography (SiO₂,EtOAc/hexane 1:1) gives the title compound; TLC (EtOAc/hexane 1:1)R_(f)=0.24; MS-ES⁺: (M+H)⁺=551.

Step 141.3:4-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

[0303] Hydrogenation of 0.50 g (0.91 mMol) of4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester in 150 ml of THF and 15 ml of1,3-dimethyl-2-imidazolidinone in the presence of 0.2 g of Pd/C (10%;“Engelhard 5125”), filtration and concentration gives the crude product.Stirring in THF/water, filtration and washing with water gives the titlecompound; MS-ES⁺: (M+H)+=431; elemental analysis for C, H, N and Fwithin 0.4% of calculated value.

Step 141.4:4-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid lithium salt

[0304] A suspension of 2.87 g (6.7 mMol) of4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester and 520 mg (12 mMol) LiOH.H₂O in 240 ml of dioxane and5 ml of water is stirred for 24 h at 120° C. The solid is dissolvedfirst, then a new precipitate is formed. Filtration at RT and washingwith dioxane and diethylether gives the title compound; HPLC (conditionssee Examples 67-78) t_(R)=13.5 min; MS-ES⁺: (M+H)+=403.

Step 141.5:(4-Ethyl-piperazin-1-yl)-{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanone

[0305] To 340 mg (0.83 mMol)4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid lithium salt in 5 ml of DMF under N₂-atmosphere, 0.38 ml (3 mMol)of N-ethylpiperazine and 0.31 ml (95%; 2 mMol) ofdiethyl-cyanphosphonate are added at 0° C. After 60 min, the suspensionis diluted with EtOAc and washed with saturated NaHCO₃-solution, waterand brine. The aqueous layers are re-extracted twice with EtOAc, theorganic layers dried (Na₂SO₄) and concentrated after adding SiO₂. Theresulting powder is put on top of a chromatography column (SiO₂) and thetitle compound eluted with EtOAc/methanol/NH₃ ^(conc.) 80:20:1; HPLC(conditions see Examples 67-78) t_(R)=10.4 min; MS-ES⁺: (M+H)⁺=499.

Examples 142-144

[0306] The following Examples are synthesized analogously to Example141: Example MS-MS⁺: HPLC ^(a) Elem. m.p. TLC Number Name (M + H)⁺ t_(R)[min] anal. ^(b) [° C.] R_(f) 142 6-[4-(4-Methyl-piperazin-1- 471 12.8CHNF ylmethyl)-phenyl]-4-(4-fluoro-2- methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidine 143 4-(4-Fluoro-2-methyl-1H-indol-5- 458 10.7280-282 0.19 ^(c) yloxy)-6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidine 144{4-[4-(4-Fluoro-2-methyl-1H- 416 10.7 0.21 ^(d)indol-5-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}- dimethyl-amine

Example 145((R)-1-Phenyl-ethyl)-[6-(4-piperazin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

[0307]

[0308]4-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl)-piperazine-1-carboxylicacid tert-butyl ester (1.8 g, 3.5 mmol) is dissolved in 150 mL ofdioxane by gentle warming. To this solution is added a solution of 4 Nhydrochloric acid in dioxane (Aldrich, Buchs, Switzerland) (5 mL, 20mmol) and the mixture stirred at 50 to 60° C. for 1 hour. The resultingsuspension is diluted with 75 mL of methanol and stirred for 1additional hour under reflux after which the mixture is cooled and thesolvent evaporated. The residue is dissolved in diluted hydrochloricacid and washed with ethyl acetate. The aqueous phase is treated withsolid potassium carbonate until basic and evaporated. The residue whichcontains inorganic salts is purified by flash chromatography usingdichloromethane/methanol 7:3 containing 1% conc. ammonia. Pure fractionswere taken up in ethyl acetate, washed with water and brine, dried withsodium sulfate and evaporated to give the title compound as a solid;m.p. 240-242° C.; MS-ES⁺: (M+H)⁺=413; TLC R_(f)(dichloromethane/methanol 7:3 containing 1% conc. ammonia) 0.35; HPLCt_(R)=6.86 min.

Example 145.14-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester

[0309]

[0310] A mixture of 1.6 g (4 mmol)[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(for the preparation see Example 9, Step 9.3 of WO 03/013541 A1) in 50ml DMF is treated with 1.56 g (8.4 mmol) N-BOC-piperazine and 2.76 g (20mmol) anhydrous potassium carbonate and the mixture heated to 65° C. for1 hour. The reaction mixture is cooled and the inorganic salts removedby filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland). The DMF isevaporated under reduced pressure and the residue purified through flashchromatography using first dichloromethane/ethanol 95:5 and thendichloromethane/ethanol 9:1. The title compound is obtained as a solid;m.p. 244-246° C.; MS-ES⁺: (M+H)⁺=513; TLC R_(f) (dichloromethane/ethanol9:1) 0.46.

Example 146 Dry-filled Capsules

[0311] 5000 capsules, each comprising as active ingredient 0.25 g of oneof the compounds of formula I mentioned in the preceding Examples, areprepared as follows: Composition active ingredient 1250 g  talcum 180 gwheat starch 120 g magnesium stearate  80 g lactose  20 g

[0312] Preparation process: The mentioned substances are pulverised andforced through a sieve of 0.6 mm mesh size. 0.33 g portions of themixture are introduced into gelatin capsules using a capsule-fillingmachine.

Example 147 Soft Capsules

[0313] 5000 soft gelatin capsules, each comprising as active ingredient0.05 g of one of the compounds of formula I mentioned in the precedingExamples, are prepared as follows: Composition active ingredient 250 gPEG 400 1 litre Tween 80 1 litre

[0314] Preparation process: The active ingredient is pulverised andsuspended in PEG 400 (polyethylene glycol having an M_(r) of fromapprox. 380 to approx. 420, Fluka, Switzerland) and Tween®80(polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind. Inc., USA,supplied by Fluka, Switzerland) and ground in a wet pulveriser to aparticle size of approx. from 1 to 3 μm, 0.43 g portions of the mixtureare then introduced into soft gelatin capsules using a capsule-fillingmachine.

Example 148 Inhibition of the tyrosine kinase activity of EGF-R (HER-1),ErbB-2 (HER-2) and VEGF receptor (KDR)

[0315] The inhibition tests are carried out as described above. The IC₅₀values for some of the compounds of formula I are given below: Compoundfrom HER-1 HER-2 KDR Example No. IC₅₀ [μM] IC₅₀ [μM] IC₅₀ [μM] 3 0.00310.008 0.0107 4 0.0031 0.0072 0.0093 5 0.0031 0.0067 0.006 6 0.007 0.0050.0127 7 0.004 0.011 0.058 8a 0.0024 0.0094 0.017 10 0.004 0.009 0.029311 0.0043 0.005 0.0497 12 0.0047 0.005 0.1387 13 0.006 0.005 0.088 140.0063 0.0085 0.0927 15 0.005 0.0065 0.0493 16a  0.0012 0.016 0.061 180.0165 0.0315 0.0245 43 0.005 0.0115 0.0515 48 0.0057 0.0075 0.058 520.0157 0.014 0.125 86 0.0055 0.016 0.105 94 0.0018 0.016 0.042 107f 0.0025 0.045 0.019 116 0.039 0.0155 0.0155

What is claimed is:
 1. A compound of formula I

wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic radicalbonded via a ring carbon atom, or a radical of the formula R₄—Y—(C=Z)-wherein R₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical, Y is either not present or lower alkyl and Z isoxygen, sulfur or imino, with the proviso that RI and R₂ are not bothhydrogen; or R₁ and R₂ together with the nitrogen atom to which they areattached form a heterocyclic radical; R₃ is a heterocyclic radical or anunsubstituted or substituted aromatic radical; G is C₁-C₇-alkylene,—C(═O)—, or C₁-C₆-alkylene-C(═O)— wherein the carbonyl group is attachedto the NR₁R₂ moiety; Q is —NH— or —O—, with the proviso that Q is —O— ifG is -C(═O)— or C₁-C₆-alkylene-C(═O)—; and X is either not present orC₁-C₇-alkylene, with the proviso that a heterocyclic radical R₃ isbonded via a ring carbon atom if X is not present; or a salt thereof. 2.A compound of formula I according to claim 1, wherein R₁ and R₂ are eachindependently of the other hydrogen, unsubstituted or substituted alkylor cycloalkyl, a heterocyclic radical bonded via a ring carbon atom, ora radical of the formula R₄—Y—(C=Z)- wherein R₄ is unsubstituted, mono-or disubstituted amino or a heterocyclic radical, Y is either notpresent or lower alkyl and Z is oxygen or sulfur or imino, with theproviso that R₁ and R₂ are not both hydrogen; or R₁ and R₂ together withthe nitrogen atom to which they are attached form a heterocyclicradical; R₃ is a heterocyclic radical or an unsubstituted or substitutedaromatic radical; G is C₁-C₇-alkylene; Q is —NH— or —O—; and X is eithernot present or C₁-C₇-alkylene, with the proviso that a heterocyclicradical R₃ is bonded via a ring carbon atom if X is not present; or asalt thereof.
 3. A compound of formula I according to claim 1, whereinR₁ and R₂ are each independently of the other hydrogen, unsubstituted orsubstituted alkyl or cycloalkyl, a heterocyclic radical bonded via aring carbon atom, or a radical of the formula R₄—Y—(C=Z)- wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radical, Yis either not present or lower alkyl and Z is oxygen, sulfur or imino,with the proviso that R₁ and R₂ are not both hydrogen; or R₁ and R₂together with the nitrogen atom to which they are attached form aheterocyclic radical; R₃ is a heterocyclic radical or an unsubstitutedor substituted aromatic radical; G is C₁-C₇-alkylene; Q is —NH—; and Xis either not present or C₁-C₇-alkylene, with the proviso that aheterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent; or a salt thereof.
 4. A compound of formula I according toclaim 3, wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted lower alkyl or C₃-C₆ cycloalkyl, aheterocyclic radical bonded via a ring carbon atom and containing up to20 carbon atoms, or?a radical of the formula R₄—Y—(C=Z)- wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radicalcontaining up to 20 carbon atoms, Y is either not present or lower alkyland Z is oxygen, with the proviso that R₁ and R₂ are not both hydrogen;or R₁ and R₂ together with the nitrogen atom to which they are attachedform a heterocyclic radical containing up to 20 carbon atoms; R₃ is aheterocyclic radical containing up to 20 carbon atoms or anunsubstituted or substituted aromatic radical having up to 20 carbonatoms; G is C₁-C₃-alkylene; Q is —NH—; and X is either not present orC₁-C₃-alkylene, with the proviso that a heterocyclic radical R₃ isbonded via a ring carbon atom if X is not present; or a salt thereof. 5.A compound of formula I according to claim 1, wherein R₁ and R₂ are eachindependently of the other hydrogen, lower alkyl, hydroxy-lower alkyl,N,N-di-lower alkylamino-lower alkyl, morpholinyl-lower alkyl,tetrahydropyranyl, or a radical of the formula R₄—Y—(C=Z)- wherein R₄ isdi-lower alkylamino, pyrrolidinyl, piperidyl, lower alkyl-piperazinyl,morpholinyl or pyridyl, Y is either not present or lower alkyl and Z isoxygen, with the proviso that R₁ and R₂ are not both hydrogen; or R₁ andR₂ together with the nitrogen atom to which they are attached form aradical selected from the group consisting of pyrrolidinyl, piperidyl,piperazinyl, lower alkyl-piperazinyl, di-lower alkyl-piperazinyl andmorpholinyl; R₃ is phenyl, benzodioxolyl, pyridyl substituted by hydroxyor lower alkoxy, indolyl substituted by halogen and lower alkyl, orphenyl substituted by one or more radicals selected independently of oneanother from the group consisting of lower alkyl, hydroxy, lower alkoxy,halogen and benzyloxy; G is —CH₂— or —C(═O)—; Q is —NH— or —O—, with theproviso that Q is —O— if G is —C(═O)—; and X is either not present,—CH₂— or —CH(CH₃)—, with the proviso that substituted pyridyl or indolylR₃ is bonded via a ring carbon atom if X is not present; or a saltthereof.
 6. A compound of formula I according to claim 3, wherein R₁ andR₂ are each independently of the other hydrogen, lower alkyl,hydroxy-lower alkyl, or a radical of the formula R₄—Y—(C=Z)- wherein R₄is di-lower alkylamino, pyrrolidinyl, piperidyl, loweralkyl-piperazinyl, morpholinyl or pyridyl, Y is either not present orlower alkyl and Z is oxygen, with the proviso that R₁ and R₂ are notboth hydrogen; or R₁ and R₂ together with the nitrogen atom to whichthey are attached form a radical selected from the group consisting ofpyrrolidinyl, piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl and morpholinyl; R₃ is phenyl, benzodioxolyl, pyridylsubstituted by hydroxy or lower alkoxy, or phenyl substituted by one ormore radicals selected independently of one another from the groupconsisting of lower alkyl, hydroxy, lower alkoxy, halogen and benzyloxy;G is —CH₂—; Q is —NH—; and X is either not present, —CH₂— or —CH(CH₃)—,with the proviso that substituted pyridyl R₃ is bonded via a ring carbonatom if X is not present; or a salt thereof.
 7. A compound of formula Iaccording to claim 1, selected from the group consisting of(3-chloro-4-fluoro-phenyl)-(6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;(3-chloro-4-fluoro-phenyl)-(6-{4-[(2-morpholin-4-yl-ethylamino)-methyl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl)-N′,N′-diethyl-ethane-1,2-diamine;(3-chloro-4-fluoro-phenyl)-{6-[4-(isopropylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(6-{4-[(2-morpholin-4-yl-ethylamino)-methyl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-((R)-1-phenyl-ethyl)-amine;((R)-1-phenyl-ethyl)-(6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;N,N-diethyl-N′-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-ethane-1,2-diamine;{6-[4-(tert-butylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;{6-[4-(isopropylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;[6-(4-ethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;[6-(4-methylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;(3-methoxy-benzyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-methoxy-benzyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-(3-methoxy-benzyl)-amine;(3-methyl-benzyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-methyl-benzyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-methyl-benzyl)-amine;[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-methyl-benzyl)-amine;(3-methyl-benzyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-methyl-benzyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-4-yl}-amine;{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-(3-methyl-benzyl)-amine;benzo[1,3]dioxol-5-yl-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(6-methoxy-pyridin-3-yl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;5-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-1H-pyridin-2-one;(6-methoxy-pyridin-3-ylmethyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(6-methoxy-pyridin-3-ylmethyl)-{6-[4-(morpholin-4-y3methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(6-methoxy-pyridin-3-ylmethyl)-{6-[4-(dimethylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-methoxy-pyridin-4-ylmethyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-methoxy-pyridin-4-ylmethyl)-6-[4-(morpholin-4-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-methoxy-pyridin-4-ylmethyl)-{6-[4-(dimethylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-methoxy-pyridin-4-ylmethyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;5-({6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one;5-({6-[(4-(dimethylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one;5-({6-[4-(4-morpholin-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamino}-methyl)-1H-pyridin-2-one;4-({6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one;4-({6-[4-(4-morpholin-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one;4-({6-[(4-(dimethylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-methyl)-1H-pyridin-2-one;4-({6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-methyl)-1H-pyridin-2-one;(2-methoxy-pyridin-4-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2-methoxy-pyridin-4-yl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-methoxy-pyridin-4-yl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;4-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-1H-pyridin-2-one;(1-phenyl-ethyl)-[6-(4-piperazin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineand pharmaceutically acceptable salts thereof.
 8. A compound of formulaI according to claim 1, selected from the group consisting of(4-ethyl-piperazin-1-yl)-{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanone;(4-methyl-piperazin-1-yl)-{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanone;{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-morpholin-4-yl-methanone;4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-N,N-dimethyl-benzamide;and pharmaceutically acceptable salts thereof.
 9. A compound of formulaI according to claim 1, selected from the group consisting of6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidine;6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidine;4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine;{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-dimethyl-amine;and pharmaceutically acceptable salts thereof.
 10. A compound of formulaI according to claim 3, selected from the group consisting of(3-chloro-4-fluoro-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-4-fluoro-phenyl)-[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-4-fluoro-phenyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(3-chloro-4-fluoro-phenyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-4-fluoro-phenyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin4-yl}-amine;(3-chloro-4-fluoro-phenyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-4-fluoro-phenyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-yl]-amine;(3-chloro-4-fluoro-phenyl)-{6-[4-(3,5-dimethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;((R)-1-phenyl-ethyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;((R)-1-phenyl-ethyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;{6-[4-(3,5-dimethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;(4-benzyloxy-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(4-benzyloxy-phenyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(4-benzyloxy-phenyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(4-benzyloxy-phenyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(4-benzyloxy-phenyl)-[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(4-benzyloxy-phenyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(4-benzyloxy-phenyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-yl]-amine;(4-benzyloxy-phenyl)-{6-[4-(3,5-dimethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;[6-(3-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;[6-(3-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;{6-[3-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;((R)-1-phenyl-ethyl)-[6-(3-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;{6-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;((R)-1-phenyl-ethyl)-[6-(3-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;[6-(3-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine;{6-[3-(3,5-dimethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine;(3-chloro-4-fluoro-phenyl)-[6-(3-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-4-fluoro-phenyl)-[6-(3-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-4-fluoro-phenyl)-{6-[3-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(3-chloro-4-fluoro-phenyl)-[6-(3-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-4-fluoro-phenyl)-{6-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(3-chloro-4-fluoro-phenyl)-[6-(3-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine;(3-chloro-4-fluoro-phenyl)-[6-(3-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide;N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-pyrrolidin-acetamide;2-morpholin-4-yl-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide;2-(4-methyl-piperazin-1-yl)-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide;2-dimethylamino-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide;2-(4-ethyl-piperazin-1-yl)-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl-benzyl}-acetamide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-(4-ethyl-piperazin-1-yl)-acetamide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-morpholin-4-yl-acetamide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-(4-methyl-piperazin-1-yl)-acetamide;N-{4-[4-(4-benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide;N-{4-[4-(4-benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-(4-methyl-piperazin-1-yl)-acetamide;N-{4-[4-(4-benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-piperidin-1yl-acetamide;N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-3-piperidin-1-yl-propionamide;3-diethylamino-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-propionamide;4-dimethylamino-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-butyramide;pyridine-2-carboxylic acid4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzylamide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-3-diethylamino-propionamide;pyridine-2-carboxylic acid4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzylamide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-4-dimethylamino-butyramide;N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-3-piperidin-1-yl-propionamide;2-dimethylamino-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide;2-(4-methyl-piperazin-1-yl)-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide;N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl-}-2-dimethylamino-acetamide;N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-(4-methyl-piperazin-1-yl)-acetamide;N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide;2-methyl-5-{6-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol;5-[6-(3-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methyl-phenol;2-methoxy-5-{6-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol;5-[6-(3-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methoxy-phenol;5-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methyl-phenol;2-methyl-5-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol;5-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methoxy-phenol;2-methoxy-5-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol;2-methoxy-5-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-phenol;[(R)-1-(4-chloro-phenyl)-ethyl]-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;[(R)-1-(4-chloro-phenyl)-ethyl]-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;[(R)-1-(4-chloro-phenyl)-ethyl]-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminehydrochloride;(3-chloro-phenyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-aminedihydrochloride;(3-chloro-phenyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminehydrochloride;2-((2-hydroxy-ethyl)-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-amino)-ethanol;(3-chloro-benzyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(3-chloro-benzyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-benzyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-benzyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-benzyl)-[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-benzyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-chloro-benzyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-chloro-benzyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2-chloro-benzyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-chloro-benzyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;(2-chloro-benzyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2-chloro-benzyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-chloro-benzyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2-chloro-benzyl)-[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2,5-dichloro-benzyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2,5-dichloro-benzyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2,5-dichloro-benzyl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2,5-dichloro-benzyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2,5-dichloro-benzyl)-[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(2,5-dichloro-benzyl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2,5-dichloro-benzyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-methoxy-benzyl)-amine;[6-(4-diethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-methoxy-benzyl)-amine;(3-methoxy-benzyl)-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(3-methoxy-benzyl)-[6-(4-piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminebenzo[1,3]dioxol-5-yl-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;benzo[1,3]dioxol-5-yl-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;benzo[1,3]dioxol-5-yl-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(6-methoxy-pyridin-3-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;(6-methoxy-pyridin-3-yl)-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(6-methoxy-pyridin-3-yl)-{6-[4-(dimethylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;(2-methoxy-pyridin-4-yl)-{6-[4-(dimethylamino-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine;5-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1H-pyridin-2-one;5-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1H-pyridin-2-one;5-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-1H-pyridin-2-one;4-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1H-pyridin-2-one;4-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1H-pyridin-2-one;4-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-1H-pyridin-2-one;and pharmaceutically acceptable salts thereof.
 11. A compound of formulaI selected from((R)-1-phenyl-ethyl)-[6-(4-piperazin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine.12. A compound of formula I, or a pharmaceutically acceptable saltthereof, according to claim 1 for use in a method for the treatment ofthe human or animal body.
 13. A pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable salt thereofaccording to claim 1, together with at least one pharmaceuticallyacceptable carrier.
 14. Use of a compound of formula I according toclaim 1, or a pharmaceutically acceptable salt thereof, for thepreparation of a pharmaceutical composition for the treatment of adisease.
 15. Use of a compound of formula I according to claim 1, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the treatment of a disease which respondsto an inhibition of a protein tyrosine kinase.
 16. A process for thepreparation of a compound of formula I according to claim 1 or of a saltof such a compound, characterized in that a) in order to prepare acompound of formula I, wherein G is C₁-C₇-alkylene and wherein R₁ and R₂are each independently of the other hydrogen, unsubstituted orsubstituted alkyl or cycloalkyl, or a heterocyclic radical bonded via aring carbon atom, with the proviso that R₁ and R₂ are not both hydrogen,or wherein R₁ and R₂ together with the nitrogen atom to which they areattached form a heterocyclic radical, a compound of the formula II

wherein Hal is halogen, G is C₁-C₇-alkylene and R₃, Q and X have themeanings as defined for a compound of formula I according to claim 1, isreacted with a compound of the formula III

wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, or a heterocyclicradical bonded via a ring carbon atom, with the proviso that R₁ and R₂are not both hydrogen, or wherein R₁ and R₂ together with the nitrogenatom to which they are attached form a heterocyclic radical; b) in orderto prepare a compound of formula I, wherein G is C₁-C₇-alkylene andwherein R₁ is a radical of the formula R₄—Y—(C=Z)- wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radical, Yis either not present or lower alkyl and Z is oxygen or sulfur, (i) acompound of the formula IV

wherein Hal is halogen, G is C₁-C₇-alkylene, Z is oxygen and theremaining substituents and symbols have the meanings as defined for acompound of formula I according to claim 1, is reacted with a compoundof the formula R₄—H wherein R₄ is unsubstituted, mono- or disubstitutedamino or a heterocyclic radical containing at least one nitrogen ringatom wherein the heterocyclic radical is attached to the hydrogen atomof R₄—H via a nitrogen ring atom, or (ii) a compound of the formula V

wherein G is C₁-C₇-alkylene and the remaining substituents and symbolshave the meanings as defined for a compound of formula I according toclaim 1, is reacted with a compound of the formula VI

wherein R₄ and Y have the meanings as defined for a compound of formulaI according to claim 1 and Z is oxygen, whereby a compound of formula Iwhich results from process b) (i) or (ii) is optionally converted intothe respective compound wherein Z is sulfur; c) in order to prepare acompound of formula I, wherein G is —C(═O)— or C₁-C₆-alkylene-C(═))—wherein the carbonyl group is attached to the NR₁R₂ moiety, a compoundof formula XI

wherein the substituents and symbols have the meanings as defined for acompound of formula I, is reacted with a compound of formula XII

wherein R₁ and R₂ have the meanings as defined for a compound of formulaI; or d) in order to prepare a compound of formula I, wherein G isC₁-C₇-alkylene, a compound of formula I, wherein G is —C(═O)— orC₁-C₆-alkylene-C(═O)— wherein the carbonyl group is attached to theNR₁R₂ moiety, is reacted with a reducing agent to produce thecorresponding compound in which G is C₁-C₇-alkylene; whereby functionalgroups which are present in the starting compounds of processes a) to d)and are not intended to take part in the reaction, are present inprotected form if necessary, and protecting groups that are present arecleaved, whereby the said starting compounds may also exist in the formof salts provided that a salt-forming group is present and a reaction insalt form is possible; and, if so desired, a compound of formula I thusobtained is converted into another compound of formula I, a freecompound of formula I is converted into a salt, an obtained salt of acompound of formula I is converted into the free compound or anothersalt, and/or a mixture of isomeric compounds of formula I is separatedinto the individual isomers.